ID FA20C_HUMAN Reviewed; 584 AA. AC Q8IXL6; A4D2Q5; L8B5W8; Q5I0W9; Q7Z4I0; Q9NPT2; DT 19-SEP-2003, integrated into UniProtKB/Swiss-Prot. DT 05-APR-2011, sequence version 2. DT 27-MAR-2024, entry version 163. DE RecName: Full=Extracellular serine/threonine protein kinase FAM20C {ECO:0000305}; DE EC=2.7.11.1 {ECO:0000269|PubMed:22582013, ECO:0000269|PubMed:23754375, ECO:0000269|PubMed:25789606, ECO:0000269|PubMed:29858230, ECO:0000269|PubMed:32149426, ECO:0000269|PubMed:34349020}; DE AltName: Full=Dentin matrix protein 4 {ECO:0000250|UniProtKB:Q5MJS3}; DE Short=DMP-4 {ECO:0000250|UniProtKB:Q5MJS3}; DE AltName: Full=Golgi casein kinase {ECO:0000303|PubMed:22582013}; DE AltName: Full=Golgi-enriched fraction casein kinase {ECO:0000303|PubMed:22582013}; DE Short=GEF-CK {ECO:0000303|PubMed:22582013}; DE Flags: Precursor; GN Name=FAM20C {ECO:0000312|HGNC:HGNC:22140}; GN Synonyms=DMP4 {ECO:0000250|UniProtKB:Q5MJS3}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Brain; RA Wu C., Ding P., Han W., Rui M., Wang Y., Song Q., Ma D.; RL Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RA Kitagawa H., Izumikawa T., Koike T.; RT "Molecular cloning and characterization of a novel xylosylkinase."; RL Submitted (FEB-2010) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12853948; DOI=10.1038/nature01782; RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K., RA Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A., RA Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H., Sun H., RA Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A., RA Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P., RA Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M., RA Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S., RA Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., RA Strowmatt C., Latreille P., Miller N., Johnson D., Murray J., RA Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., RA Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., RA Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E., RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E., RA Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A., RA Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A., RA Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R., RA McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H., RA Wilson R.K.; RT "The DNA sequence of human chromosome 7."; RL Nature 424:157-164(2003). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12690205; DOI=10.1126/science.1083423; RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K., RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R., RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A., RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S., Kwasnicka D., RA Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., Lu F., Zeesman S., RA Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., Weksberg R., RA Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., Rahman N., RA Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., Belloni E., RA Shaffer L.G., Pober B., Morton C.C., Gusella J.F., Bruns G.A.P., Korf B.R., RA Quade B.J., Ligon A.H., Ferguson H., Higgins A.W., Leach N.T., RA Herrick S.R., Lemyre E., Farra C.G., Kim H.-G., Summers A.M., Gripp K.W., RA Roberts W., Szatmari P., Winsor E.J.T., Grzeschik K.-H., Teebi A., RA Minassian B.A., Kere J., Armengol L., Pujana M.A., Estivill X., RA Wilson M.D., Koop B.F., Tosi S., Moore G.E., Boright A.P., Zlotorynski E., RA Kerem B., Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H., RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., Mural R.J., RA Adams M.D., Tsui L.-C.; RT "Human chromosome 7: DNA sequence and biology."; RL Science 300:767-772(2003). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Brain; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP PROTEIN SEQUENCE OF N-TERMINUS, FUNCTION, SUBCELLULAR LOCATION, RP AUTOPHOSPHORYLATION, GLYCOSYLATION AT ASN-101; ASN-335 AND ASN-470, AND RP MUTAGENESIS OF 93-LEU--ASP-95; ASN-101; ASN-335; ASN-470 AND ASP-478. RX PubMed=26091039; DOI=10.1016/j.cell.2015.05.028; RA Tagliabracci V.S., Wiley S.E., Guo X., Kinch L.N., Durrant E., Wen J., RA Xiao J., Cui J., Nguyen K.B., Engel J.L., Coon J.J., Grishin N., RA Pinna L.A., Pagliarini D.J., Dixon J.E.; RT "A single kinase generates the majority of the secreted phosphoproteome."; RL Cell 161:1619-1632(2015). RN [9] RP PROTEIN SEQUENCE OF N-TERMINUS, FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, RP INTERACTION WITH MBTPS1; SEC23A AND SEC24A, SUBCELLULAR LOCATION, TOPOLOGY, RP AUTOPHOSPHORYLATION, PHOSPHORYLATION AT SER-106, AND MUTAGENESIS OF RP 28-ASP--PRO-31; CYS-46; CYS-48; ARG-89; ILE-90; LEU-91; GLN-92; SER-106 AND RP ASP-478. RX PubMed=34349020; DOI=10.1073/pnas.2100133118; RA Chen X., Zhang J., Liu P., Wei Y., Wang X., Xiao J., Wang C.C., Wang L.; RT "Proteolytic processing of secretory pathway kinase Fam20C by site-1 RT protease promotes biomineralization."; RL Proc. Natl. Acad. Sci. U.S.A. 118:0-0(2021). RN [10] RP TISSUE SPECIFICITY. RX PubMed=15676076; DOI=10.1186/1471-2164-6-11; RA Nalbant D., Youn H., Nalbant S.I., Sharma S., Cobos E., Beale E.G., Du Y., RA Williams S.C.; RT "FAM20: an evolutionarily conserved family of secreted proteins expressed RT in hematopoietic cells."; RL BMC Genomics 6:11-11(2005). RN [11] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-470. RC TISSUE=Liver; RX PubMed=19159218; DOI=10.1021/pr8008012; RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.; RT "Glycoproteomics analysis of human liver tissue by combination of multiple RT enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [12] RP FUNCTION, CATALYTIC ACTIVITY, MANGANESE-BINDING, MUTAGENESIS OF ASP-478, RP VARIANTS RNS ASN-258; ARG-280; SER-328; ARG-379; GLU-379; ARG-388; ASN-451 RP AND TRP-549, AND CHARACTERIZATION OF VARIANTS RNS SER-328 AND ASN-451. RX PubMed=22582013; DOI=10.1126/science.1217817; RA Tagliabracci V.S., Engel J.L., Wen J., Wiley S.E., Worby C.A., Kinch L.N., RA Xiao J., Grishin N.V., Dixon J.E.; RT "Secreted kinase phosphorylates extracellular proteins that regulate RT biomineralization."; RL Science 336:1150-1153(2012). RN [13] RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, COFACTOR, RP ACTIVE SITE, AND MUTAGENESIS OF LYS-271; LYS-285; GLU-306; GLU-311; RP ARG-408; ASP-458 AND ASP-458. RX PubMed=23754375; DOI=10.1073/pnas.1309211110; RA Xiao J., Tagliabracci V.S., Wen J., Kim S.A., Dixon J.E.; RT "Crystal structure of the Golgi casein kinase."; RL Proc. Natl. Acad. Sci. U.S.A. 110:10574-10579(2013). RN [14] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, INTERACTION WITH FAM20A, RP MUTAGENESIS OF GLU-306 AND ASP-478, VARIANTS RNS MET-268 AND SER-328, AND RP CHARACTERIZATION OF VARIANTS RNS MET-268 AND SER-328. RX PubMed=25789606; DOI=10.7554/elife.06120; RA Cui J., Xiao J., Tagliabracci V.S., Wen J., Rahdar M., Dixon J.E.; RT "A secretory kinase complex regulates extracellular protein RT phosphorylation."; RL Elife 4:0-0(2015). RN [15] RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF ASP-478. RX PubMed=29858230; DOI=10.15252/embj.201798699; RA Zhang J., Zhu Q., Wang X., Yu J., Chen X., Wang J., Wang X., Xiao J., RA Wang C.C., Wang L.; RT "Secretory kinase Fam20C tunes endoplasmic reticulum redox state via RT phosphorylation of Ero1alpha."; RL EMBO J. 37:0-0(2018). RN [16] RP FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION. RX PubMed=32149426; DOI=10.15252/embj.2019103841; RA Yu J., Li T., Liu Y., Wang X., Zhang J., Wang X., Shi G., Lou J., Wang L., RA Wang C.C., Wang L.; RT "Phosphorylation switches protein disulfide isomerase activity to maintain RT proteostasis and attenuate ER stress."; RL EMBO J. 39:e103841-e103841(2020). RN [17] RP VARIANTS RNS ARG-379; GLU-379; ARG-388 AND TRP-549. RX PubMed=17924334; DOI=10.1086/522240; RA Simpson M.A., Hsu R., Keir L.S., Hao J., Sivapalan G., Ernst L.M., RA Zackai E.H., Al-Gazali L.I., Hulskamp G., Kingston H.M., Prescott T.E., RA Ion A., Patton M.A., Murday V., George A., Crosby A.H.; RT "Mutations in FAM20C are associated with lethal osteosclerotic bone RT dysplasia (Raine syndrome), highlighting a crucial molecule in bone RT development."; RL Am. J. Hum. Genet. 81:906-912(2007). CC -!- FUNCTION: Golgi serine/threonine protein kinase that phosphorylates CC secretory pathway proteins within Ser-x-Glu/pSer motifs and plays a key CC role in biomineralization of bones and teeth (PubMed:22582013, CC PubMed:23754375, PubMed:25789606). Constitutes the main protein kinase CC for extracellular proteins, generating the majority of the CC extracellular phosphoproteome (PubMed:26091039). Mainly phosphorylates CC proteins within the Ser-x-Glu/pSer motif, but also displays a broader CC substrate specificity (PubMed:26091039). Phosphorylates ERO1A, CC enhancing its activity which is required to maintain endoplasmic CC reticulum redox homeostasis and for oxidative protein folding CC (PubMed:29858230, PubMed:34349020). During endoplasmic reticulum CC stress, phosphorylates P4HB/PDIA1 which induces a functional switch, CC causing P4HB to change from an oxidoreductase to a molecular chaperone CC (PubMed:32149426). This is critical to maintain ER proteostasis and CC reduce cell death under ER stress (PubMed:32149426). Phosphorylation of CC P4HB also promotes its interaction with ERN1, leading to reduced CC activity of ERN1, a key sensor for the endoplasmic reticulum unfolded CC protein response (PubMed:32149426). Required for osteoblast CC differentiation and mineralization (PubMed:34349020). Phosphorylates CC casein as well as a number of proteins involved in biomineralization CC such as AMELX, AMTN, ENAM and SPP1/OPN (PubMed:22582013, CC PubMed:25789606, PubMed:34349020). In addition to its role in CC biomineralization, also plays a role in lipid homeostasis, wound CC healing and cell migration and adhesion (PubMed:26091039). CC {ECO:0000269|PubMed:22582013, ECO:0000269|PubMed:23754375, CC ECO:0000269|PubMed:25789606, ECO:0000269|PubMed:26091039, CC ECO:0000269|PubMed:29858230, ECO:0000269|PubMed:32149426, CC ECO:0000269|PubMed:34349020}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; CC Evidence={ECO:0000269|PubMed:22582013, ECO:0000269|PubMed:23754375, CC ECO:0000269|PubMed:25789606, ECO:0000269|PubMed:29858230, CC ECO:0000269|PubMed:32149426, ECO:0000269|PubMed:34349020}; CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; CC EC=2.7.11.1; Evidence={ECO:0000269|PubMed:22582013, CC ECO:0000269|PubMed:23754375, ECO:0000269|PubMed:25789606}; CC -!- COFACTOR: CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035; CC Evidence={ECO:0000269|PubMed:23754375, ECO:0000305|PubMed:22582013}; CC -!- ACTIVITY REGULATION: Serine/threonine protein kinase activity is CC increased upon interaction with FAM20A. {ECO:0000269|PubMed:25789606}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=0.8 uM for manganese/ATP {ECO:0000269|PubMed:23754375}; CC -!- SUBUNIT: Homodimer; disulfide-linked (PubMed:34349020). Interacts with CC FAM20A; probably forming a heterotetramer of 2 subunits of FAM20A and 2 CC subunits of FAM20C (PubMed:25789606). Interacts with protease CC MBTPS1/S1P; the interaction results in FAM20C cleavage and secretion CC (PubMed:34349020). Interacts with COPII components SEC23A and SEC24A; CC transport of FAM20C from the endoplasmic reticulum to the Golgi is CC likely to be mediated by COPII vesicles (PubMed:34349020). CC {ECO:0000269|PubMed:25789606, ECO:0000269|PubMed:34349020}. CC -!- INTERACTION: CC Q8IXL6; Q9NP70: AMBN; NbExp=2; IntAct=EBI-7147442, EBI-11893530; CC Q8IXL6; Q6UX39: AMTN; NbExp=2; IntAct=EBI-7147442, EBI-11892684; CC Q8IXL6; O14791: APOL1; NbExp=2; IntAct=EBI-7147442, EBI-1221934; CC Q8IXL6; P05060: CHGB; NbExp=2; IntAct=EBI-7147442, EBI-712619; CC Q8IXL6; Q9NRM1: ENAM; NbExp=2; IntAct=EBI-7147442, EBI-11892601; CC Q8IXL6; Q96MK3: FAM20A; NbExp=3; IntAct=EBI-7147442, EBI-11892970; CC Q8IXL6; P02671: FGA; NbExp=2; IntAct=EBI-7147442, EBI-348571; CC Q8IXL6; P08833: IGFBP1; NbExp=2; IntAct=EBI-7147442, EBI-13646303; CC Q8IXL6; P02810: PRH2; NbExp=2; IntAct=EBI-7147442, EBI-738601; CC Q8IXL6; P01008: SERPINC1; NbExp=2; IntAct=EBI-7147442, EBI-1039832; CC Q8IXL6; P10451: SPP1; NbExp=3; IntAct=EBI-7147442, EBI-723648; CC Q8IXL6; PRO_0000020321 [P10451]: SPP1; NbExp=2; IntAct=EBI-7147442, EBI-11893188; CC Q8IXL6; P02666: CSN2; Xeno; NbExp=3; IntAct=EBI-7147442, EBI-5260183; CC -!- SUBCELLULAR LOCATION: Golgi apparatus membrane CC {ECO:0000269|PubMed:32149426, ECO:0000269|PubMed:34349020}; Single-pass CC type II membrane protein {ECO:0000269|PubMed:34349020}. Secreted CC {ECO:0000269|PubMed:26091039}. Endoplasmic reticulum CC {ECO:0000269|PubMed:32149426}. Note=Resides in the Golgi apparatus CC membrane and is secreted following propeptide cleavage CC (PubMed:34349020). Retained in the endoplasmic reticulum (ER) in CC response to ER stress where it phosphorylates P4HB (PubMed:32149426). CC {ECO:0000269|PubMed:32149426, ECO:0000269|PubMed:34349020}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q8IXL6-1; Sequence=Displayed; CC Name=2; CC IsoId=Q8IXL6-2; Sequence=VSP_040834; CC -!- TISSUE SPECIFICITY: Widely expressed. {ECO:0000269|PubMed:15676076}. CC -!- PTM: N-glycosylation is required for folding. CC {ECO:0000305|PubMed:26091039}. CC -!- PTM: Autophosphorylated. {ECO:0000269|PubMed:26091039, CC ECO:0000269|PubMed:34349020}. CC -!- PTM: Propeptide cleavage by MBTPS1/S1P promotes FAM20C secretion and CC maximal kinase activity which is essential for efficient osteoblast CC differentiation and biomineralization. {ECO:0000269|PubMed:34349020}. CC -!- DISEASE: Raine syndrome (RNS) [MIM:259775]: An autosomal recessive CC osteosclerotic bone dysplasia with neonatal lethal outcome, although CC some patients survive into childhood. Clinical features include CC generalized increase in the density of all bones and a marked increase CC in the ossification of the skull, craniofacial dysplasia and CC microcephaly. {ECO:0000269|PubMed:17924334, CC ECO:0000269|PubMed:22582013, ECO:0000269|PubMed:25789606}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the FAM20 family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAH40074.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=EAL23705.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF533706; AAQ09019.1; -; mRNA. DR EMBL; AB545605; BAM78534.1; -; mRNA. DR EMBL; AC093627; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC145676; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC187652; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH236966; EAL23705.1; ALT_INIT; Genomic_DNA. DR EMBL; CH471144; EAW87149.1; -; Genomic_DNA. DR EMBL; BC040074; AAH40074.1; ALT_INIT; mRNA. DR EMBL; BC087853; AAH87853.1; -; mRNA. DR EMBL; AL390147; CAB99089.2; -; mRNA. DR CCDS; CCDS47522.1; -. [Q8IXL6-1] DR PIR; T51872; T51872. DR RefSeq; NP_064608.2; NM_020223.3. [Q8IXL6-1] DR PDB; 5YH3; X-ray; 3.30 A; C/D=141-578. DR PDBsum; 5YH3; -. DR AlphaFoldDB; Q8IXL6; -. DR SMR; Q8IXL6; -. DR BioGRID; 121294; 191. DR IntAct; Q8IXL6; 76. DR MINT; Q8IXL6; -. DR STRING; 9606.ENSP00000322323; -. DR BindingDB; Q8IXL6; -. DR ChEMBL; CHEMBL4879492; -. DR GlyConnect; 1230; 11 N-Linked glycans (2 sites). DR GlyCosmos; Q8IXL6; 8 sites, 12 glycans. DR GlyGen; Q8IXL6; 12 sites, 11 N-linked glycans (2 sites), 2 O-linked glycans (9 sites). DR iPTMnet; Q8IXL6; -. DR PhosphoSitePlus; Q8IXL6; -. DR BioMuta; FAM20C; -. DR DMDM; 327478506; -. DR EPD; Q8IXL6; -. DR jPOST; Q8IXL6; -. DR MassIVE; Q8IXL6; -. DR MaxQB; Q8IXL6; -. DR PaxDb; 9606-ENSP00000322323; -. DR PeptideAtlas; Q8IXL6; -. DR ProteomicsDB; 71022; -. [Q8IXL6-1] DR ProteomicsDB; 71023; -. [Q8IXL6-2] DR Antibodypedia; 5456; 166 antibodies from 25 providers. DR DNASU; 56975; -. DR Ensembl; ENST00000313766.6; ENSP00000322323.5; ENSG00000177706.9. [Q8IXL6-1] DR Ensembl; ENST00000672066.1; ENSP00000499851.1; ENSG00000288499.1. [Q8IXL6-1] DR GeneID; 56975; -. DR KEGG; hsa:56975; -. DR MANE-Select; ENST00000313766.6; ENSP00000322323.5; NM_020223.4; NP_064608.2. DR UCSC; uc003sip.4; human. [Q8IXL6-1] DR AGR; HGNC:22140; -. DR CTD; 56975; -. DR DisGeNET; 56975; -. DR GeneCards; FAM20C; -. DR HGNC; HGNC:22140; FAM20C. DR HPA; ENSG00000177706; Low tissue specificity. DR MalaCards; FAM20C; -. DR MIM; 259775; phenotype. DR MIM; 611061; gene. DR neXtProt; NX_Q8IXL6; -. DR OpenTargets; ENSG00000177706; -. DR Orphanet; 1832; Lethal osteosclerotic bone dysplasia. DR PharmGKB; PA134898453; -. DR VEuPathDB; HostDB:ENSG00000177706; -. DR eggNOG; KOG3829; Eukaryota. DR GeneTree; ENSGT00950000182951; -. DR HOGENOM; CLU_028926_2_0_1; -. DR InParanoid; Q8IXL6; -. DR OMA; AAENQDW; -. DR OrthoDB; 5382325at2759; -. DR PhylomeDB; Q8IXL6; -. DR TreeFam; TF313276; -. DR PathwayCommons; Q8IXL6; -. DR Reactome; R-HSA-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs). DR Reactome; R-HSA-8957275; Post-translational protein phosphorylation. DR SABIO-RK; Q8IXL6; -. DR SignaLink; Q8IXL6; -. DR SIGNOR; Q8IXL6; -. DR BioGRID-ORCS; 56975; 16 hits in 1160 CRISPR screens. DR GeneWiki; FAM20C; -. DR GenomeRNAi; 56975; -. DR Pharos; Q8IXL6; Tbio. DR PRO; PR:Q8IXL6; -. DR Proteomes; UP000005640; Chromosome 7. DR RNAct; Q8IXL6; Protein. DR Bgee; ENSG00000177706; Expressed in right lobe of liver and 99 other cell types or tissues. DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB. DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA. DR GO; GO:0000139; C:Golgi membrane; IDA:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0005509; F:calcium ion binding; IEA:Ensembl. DR GO; GO:0030145; F:manganese ion binding; IDA:UniProtKB. DR GO; GO:0002020; F:protease binding; IPI:UniProtKB. DR GO; GO:0004672; F:protein kinase activity; IDA:UniProtKB. DR GO; GO:0043621; F:protein self-association; IDA:UniProtKB. DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB. DR GO; GO:0031214; P:biomineral tissue development; IMP:UniProtKB. DR GO; GO:0097187; P:dentinogenesis; IEA:Ensembl. DR GO; GO:0070166; P:enamel mineralization; IBA:GO_Central. DR GO; GO:0071895; P:odontoblast differentiation; IEA:Ensembl. DR GO; GO:0036179; P:osteoclast maturation; IEA:Ensembl. DR GO; GO:0030501; P:positive regulation of bone mineralization; IEA:Ensembl. DR GO; GO:0045669; P:positive regulation of osteoblast differentiation; IEA:Ensembl. DR GO; GO:0043687; P:post-translational protein modification; TAS:Reactome. DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB. DR GO; GO:0019538; P:protein metabolic process; TAS:Reactome. DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB. DR GO; GO:0040036; P:regulation of fibroblast growth factor receptor signaling pathway; IEA:Ensembl. DR GO; GO:0051174; P:regulation of phosphorus metabolic process; IEA:Ensembl. DR CDD; cd10471; FAM20C_C; 1. DR InterPro; IPR024869; FAM20. DR InterPro; IPR009581; FAM20_C. DR PANTHER; PTHR12450; DENTIN MATRIX PROTEIN 4 PROTEIN FAM20; 1. DR PANTHER; PTHR12450:SF11; EXTRACELLULAR SERINE_THREONINE PROTEIN KINASE FAM20C; 1. DR Pfam; PF06702; Fam20C; 1. DR Genevisible; Q8IXL6; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; ATP-binding; Biomineralization; KW Calcium; Direct protein sequencing; Disease variant; Disulfide bond; KW Endoplasmic reticulum; Glycoprotein; Golgi apparatus; Kinase; Manganese; KW Membrane; Metal-binding; Nucleotide-binding; Phosphoprotein; KW Reference proteome; Secreted; Serine/threonine-protein kinase; KW Signal-anchor; Transferase; Transmembrane; Transmembrane helix. FT PROPEP 1..92 FT /evidence="ECO:0000269|PubMed:26091039, FT ECO:0000269|PubMed:34349020" FT /id="PRO_0000433883" FT CHAIN 93..584 FT /note="Extracellular serine/threonine protein kinase FT FAM20C" FT /id="PRO_0000008747" FT TOPO_DOM 1..10 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 11..31 FT /note="Helical; Signal-anchor for type II membrane protein" FT /evidence="ECO:0000255" FT TOPO_DOM 32..584 FT /note="Lumenal" FT /evidence="ECO:0000305" FT REGION 62..81 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 94..159 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 354..565 FT /note="Kinase domain" FT /evidence="ECO:0000305|PubMed:22582013" FT COMPBIAS 118..144 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 458 FT /evidence="ECO:0000269|PubMed:23754375" FT BINDING 269 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000250|UniProtKB:Q9XTW2" FT BINDING 285 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000250|UniProtKB:Q9XTW2" FT BINDING 306 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000250|UniProtKB:Q9XTW2" FT BINDING 306 FT /ligand="Mn(2+)" FT /ligand_id="ChEBI:CHEBI:29035" FT /evidence="ECO:0000250|UniProtKB:Q9XTW2" FT BINDING 389..392 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000250|UniProtKB:Q9XTW2" FT BINDING 463 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000250|UniProtKB:Q9XTW2" FT BINDING 478 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000250|UniProtKB:Q9XTW2" FT BINDING 478 FT /ligand="Mn(2+)" FT /ligand_id="ChEBI:CHEBI:29035" FT /evidence="ECO:0000305|PubMed:22582013" FT SITE 92..93 FT /note="Cleavage; by MBTPS1" FT /evidence="ECO:0000269|PubMed:34349020" FT MOD_RES 106 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:34349020" FT CARBOHYD 101 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:26091039" FT CARBOHYD 335 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:26091039" FT CARBOHYD 470 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19159218, FT ECO:0000269|PubMed:26091039" FT DISULFID 46 FT /note="Interchain" FT /evidence="ECO:0000269|PubMed:34349020" FT DISULFID 48 FT /note="Interchain" FT /evidence="ECO:0000269|PubMed:34349020" FT DISULFID 362..378 FT /evidence="ECO:0000250|UniProtKB:Q9XTW2" FT DISULFID 367..371 FT /evidence="ECO:0000250|UniProtKB:Q9XTW2" FT DISULFID 426..500 FT /evidence="ECO:0000250|UniProtKB:Q9XTW2" FT DISULFID 501..560 FT /evidence="ECO:0000250|UniProtKB:Q9XTW2" FT VAR_SEQ 1..332 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:17974005" FT /id="VSP_040834" FT VARIANT 258 FT /note="I -> N (in RNS)" FT /evidence="ECO:0000269|PubMed:22582013" FT /id="VAR_073660" FT VARIANT 268 FT /note="T -> M (in RNS; mild non-lethal form; decreased FT protein kinase activity; dbSNP:rs778899041)" FT /evidence="ECO:0000269|PubMed:25789606" FT /id="VAR_073661" FT VARIANT 280 FT /note="G -> R (in RNS; dbSNP:rs779708323)" FT /evidence="ECO:0000269|PubMed:22582013" FT /id="VAR_073662" FT VARIANT 328 FT /note="P -> S (in RNS; mild non-lethal form; decreased FT protein kinase activity; FAM20A is still able to increase FT remaining protein kinase activity; dbSNP:rs797044462)" FT /evidence="ECO:0000269|PubMed:22582013, FT ECO:0000269|PubMed:25789606" FT /id="VAR_073663" FT VARIANT 379 FT /note="G -> E (in RNS; dbSNP:rs796051852)" FT /evidence="ECO:0000269|PubMed:17924334, FT ECO:0000269|PubMed:22582013" FT /id="VAR_037530" FT VARIANT 379 FT /note="G -> R (in RNS)" FT /evidence="ECO:0000269|PubMed:17924334, FT ECO:0000269|PubMed:22582013" FT /id="VAR_037531" FT VARIANT 388 FT /note="L -> R (in RNS; dbSNP:rs796051849)" FT /evidence="ECO:0000269|PubMed:17924334, FT ECO:0000269|PubMed:22582013" FT /id="VAR_037532" FT VARIANT 451 FT /note="D -> N (in RNS; mild non-lethal form; decreased FT protein kinase activity)" FT /evidence="ECO:0000269|PubMed:22582013" FT /id="VAR_073664" FT VARIANT 549 FT /note="R -> W (in RNS; dbSNP:rs796051850)" FT /evidence="ECO:0000269|PubMed:17924334, FT ECO:0000269|PubMed:22582013" FT /id="VAR_037533" FT MUTAGEN 28..31 FT /note="DLLP->AAAA: Loss of membrane localization with more FT efficient secretion and loss of propeptide cleavage. FT Reduced oligomerization." FT /evidence="ECO:0000269|PubMed:34349020" FT MUTAGEN 46 FT /note="C->S: No effect on homodimer formation. Complete FT disruption of homodimer formation but no effect on FT secretion; when associated with S-48." FT /evidence="ECO:0000269|PubMed:34349020" FT MUTAGEN 48 FT /note="C->S: No effect on homodimer formation. Complete FT disruption of homodimer formation but no effect on FT secretion; when associated with S-46." FT /evidence="ECO:0000269|PubMed:34349020" FT MUTAGEN 89 FT /note="R->A: Impaired secretion. Loss of ability to promote FT osteoblast differentiation; when associated with A-92." FT /evidence="ECO:0000269|PubMed:34349020" FT MUTAGEN 90 FT /note="I->A: No effect on secretion." FT /evidence="ECO:0000269|PubMed:34349020" FT MUTAGEN 91..93 FT /note="LQD->AAA: No effect on secretion or activity." FT /evidence="ECO:0000269|PubMed:26091039" FT MUTAGEN 91 FT /note="L->S: Impaired secretion." FT /evidence="ECO:0000269|PubMed:34349020" FT MUTAGEN 92 FT /note="Q->A: Impaired secretion. Loss of ability to promote FT osteoblast differentiation; when associated with A-89." FT /evidence="ECO:0000269|PubMed:34349020" FT MUTAGEN 101 FT /note="N->A: Impaired secretion; when associated with A-335 FT and A-470." FT /evidence="ECO:0000269|PubMed:26091039" FT MUTAGEN 106 FT /note="S->A: Abolishes phosphorylation." FT /evidence="ECO:0000269|PubMed:34349020" FT MUTAGEN 271 FT /note="K->A: Reduced kinase activity." FT /evidence="ECO:0000269|PubMed:23754375" FT MUTAGEN 285 FT /note="K->A: Reduced kinase activity." FT /evidence="ECO:0000269|PubMed:23754375" FT MUTAGEN 306 FT /note="E->A,Q: Strongly reduced kinase activity." FT /evidence="ECO:0000269|PubMed:23754375, FT ECO:0000269|PubMed:25789606" FT MUTAGEN 311 FT /note="E->A: Reduced kinase activity." FT /evidence="ECO:0000269|PubMed:23754375" FT MUTAGEN 335 FT /note="N->A: Impaired secretion; when associated with A-101 FT and A-470." FT /evidence="ECO:0000269|PubMed:26091039" FT MUTAGEN 408 FT /note="R->A: Reduced kinase activity." FT /evidence="ECO:0000269|PubMed:23754375" FT MUTAGEN 458 FT /note="D->A: Abrogates kinase activity." FT /evidence="ECO:0000269|PubMed:23754375" FT MUTAGEN 470 FT /note="N->A: Impaired secretion; when associated with A-101 FT and A-335." FT /evidence="ECO:0000269|PubMed:26091039" FT MUTAGEN 478 FT /note="D->A: Unable to bind manganese. Abrogates kinase FT activity. Loss of ERO1A phosphorylation. Loss of FT autophosphorylation. Loss of ability to promote osteoblast FT differentiation." FT /evidence="ECO:0000269|PubMed:22582013, FT ECO:0000269|PubMed:23754375, ECO:0000269|PubMed:25789606, FT ECO:0000269|PubMed:26091039, ECO:0000269|PubMed:29858230, FT ECO:0000269|PubMed:34349020" FT CONFLICT 274..288 FT /note="MTFQNYGQALFKPMK -> FLSDKPFLFLSCFLR (in Ref. 6; FT CAB99089)" FT /evidence="ECO:0000305" FT CONFLICT 564 FT /note="N -> D (in Ref. 5; AAH87853 and 6; CAB99089)" FT /evidence="ECO:0000305" FT HELIX 160..164 FT /evidence="ECO:0007829|PDB:5YH3" FT HELIX 168..170 FT /evidence="ECO:0007829|PDB:5YH3" FT TURN 179..181 FT /evidence="ECO:0007829|PDB:5YH3" FT STRAND 182..184 FT /evidence="ECO:0007829|PDB:5YH3" FT HELIX 225..231 FT /evidence="ECO:0007829|PDB:5YH3" FT STRAND 237..239 FT /evidence="ECO:0007829|PDB:5YH3" FT HELIX 244..255 FT /evidence="ECO:0007829|PDB:5YH3" FT STRAND 258..263 FT /evidence="ECO:0007829|PDB:5YH3" FT STRAND 272..276 FT /evidence="ECO:0007829|PDB:5YH3" FT STRAND 281..286 FT /evidence="ECO:0007829|PDB:5YH3" FT HELIX 301..303 FT /evidence="ECO:0007829|PDB:5YH3" FT HELIX 308..320 FT /evidence="ECO:0007829|PDB:5YH3" FT STRAND 329..335 FT /evidence="ECO:0007829|PDB:5YH3" FT TURN 336..340 FT /evidence="ECO:0007829|PDB:5YH3" FT HELIX 341..343 FT /evidence="ECO:0007829|PDB:5YH3" FT HELIX 347..350 FT /evidence="ECO:0007829|PDB:5YH3" FT STRAND 361..363 FT /evidence="ECO:0007829|PDB:5YH3" FT STRAND 368..370 FT /evidence="ECO:0007829|PDB:5YH3" FT HELIX 373..375 FT /evidence="ECO:0007829|PDB:5YH3" FT STRAND 380..390 FT /evidence="ECO:0007829|PDB:5YH3" FT TURN 419..421 FT /evidence="ECO:0007829|PDB:5YH3" FT TURN 423..425 FT /evidence="ECO:0007829|PDB:5YH3" FT HELIX 426..429 FT /evidence="ECO:0007829|PDB:5YH3" FT TURN 433..436 FT /evidence="ECO:0007829|PDB:5YH3" FT HELIX 438..454 FT /evidence="ECO:0007829|PDB:5YH3" FT STRAND 461..463 FT /evidence="ECO:0007829|PDB:5YH3" FT TURN 467..470 FT /evidence="ECO:0007829|PDB:5YH3" FT HELIX 491..494 FT /evidence="ECO:0007829|PDB:5YH3" FT HELIX 495..500 FT /evidence="ECO:0007829|PDB:5YH3" FT HELIX 505..513 FT /evidence="ECO:0007829|PDB:5YH3" FT HELIX 517..519 FT /evidence="ECO:0007829|PDB:5YH3" FT HELIX 521..528 FT /evidence="ECO:0007829|PDB:5YH3" FT STRAND 530..534 FT /evidence="ECO:0007829|PDB:5YH3" FT HELIX 540..564 FT /evidence="ECO:0007829|PDB:5YH3" FT TURN 567..569 FT /evidence="ECO:0007829|PDB:5YH3" SQ SEQUENCE 584 AA; 66234 MW; ECD278B5EA681FEF CRC64; MKMMLVRRFR VLILMVFLVA CALHIALDLL PRLERRGARP SGEPGCSCAQ PAAEVAAPGW AQVRGRPGEP PAASSAAGDA GWPNKHTLRI LQDFSSDPSS NLSSHSLEKL PPAAEPAERA LRGRDPGALR PHDPAHRPLL RDPGPRRSES PPGPGGDASL LARLFEHPLY RVAVPPLTEE DVLFNVNSDT RLSPKAAENP DWPHAGAEGA EFLSPGEAAV DSYPNWLKFH IGINRYELYS RHNPAIEALL HDLSSQRITS VAMKSGGTQL KLIMTFQNYG QALFKPMKQT REQETPPDFF YFSDYERHNA EIAAFHLDRI LDFRRVPPVA GRMVNMTKEI RDVTRDKKLW RTFFISPANN ICFYGECSYY CSTEHALCGK PDQIEGSLAA FLPDLSLAKR KTWRNPWRRS YHKRKKAEWE VDPDYCEEVK QTPPYDSSHR ILDVMDMTIF DFLMGNMDRH HYETFEKFGN ETFIIHLDNG RGFGKYSHDE LSILVPLQQC CRIRKSTYLR LQLLAKEEYK LSLLMAESLR GDQVAPVLYQ PHLEALDRRL RVVLKAVRDC VERNGLHSVV DDDLDTEHRA ASAR //