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Protein

S-adenosylhomocysteine hydrolase-like protein 1

Gene

AHCYL1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Multifaceted cellular regulator which coordinates several essential cellular functions including regulation of epithelial HCO3- and fluid secretion, mRNA processing and DNA replication. Regulates ITPR1 sensitivity to inositol 1,4,5-trisphosphate competing for the common binding site and acting as endogenous 'pseudoligand' whose inhibitory activity can be modulated by its phosphorylation status. In the pancreatic and salivary ducts, at resting state, attenuates inositol 1,4,5-trisphosphate-induced calcium release by interacting with ITPR1 (PubMed:16793548). When extracellular stimuli induce ITPR1 phosphorylation or inositol 1,4,5-trisphosphate production, dissociates of ITPR1 to interact with CFTR and SLC26A6 mediating their synergistic activation by calcium and cAMP that stimulates the epithelial secretion of electrolytes and fluid (By similarity). Also activates basolateral SLC4A4 isoform 1 to coordinate fluid and HCO3- secretion (PubMed:16769890). Inhibits the effect of STK39 on SLC4A4 and CFTR by recruiting PP1 phosphatase which activates SLC4A4, SLC26A6 and CFTR through dephosphorylation (By similarity). Mediates the induction of SLC9A3 surface expression produced by Angiotensin-2 (PubMed:20584908). Depending on the cell type, activates SLC9A3 in response to calcium or reverses SLC9A3R2-dependent calcium inhibition (PubMed:18829453). May modulate the polyadenylation state of specific mRNAs, both by controlling the subcellular location of FIP1L1 and by inhibiting PAPOLA activity, in response to a stimulus that alters its phosphorylation state (PubMed:19224921). Acts as a (dATP)-dependent inhibitor of ribonucleotide reductase large subunit RRM1, controlling the endogenous dNTP pool and ensuring normal cell cycle progression (PubMed:25237103). In vitro does not exhibit any S-adenosyl-L-homocysteine hydrolase activity (By similarity).By similarity6 Publications

Miscellaneous

Ablation of expression in HeLa cells causes imbalanced dNTP pools and altered cell cycle progression.1 Publication

Cofactori

NAD+1 PublicationNote: Binds 1 NAD+ per subunit.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei155SubstrateBy similarity1
Binding sitei229SubstrateBy similarity1
Binding sitei254SubstrateBy similarity1
Binding sitei284SubstrateBy similarity1
Binding sitei288SubstrateBy similarity1
Binding sitei341NAD1 Publication1
Binding sitei376NAD1 Publication1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi318 – 322NAD1 Publication5
Nucleotide bindingi397 – 399NAD1 Publication3

GO - Molecular functioni

  • identical protein binding Source: IntAct
  • RNA binding Source: UniProtKB-KW

GO - Biological processi

  • angiotensin-activated signaling pathway Source: UniProtKB
  • epithelial fluid transport Source: Ensembl
  • mRNA polyadenylation Source: UniProtKB
  • one-carbon metabolic process Source: UniProtKB-KW
  • positive regulation of sodium ion transport Source: UniProtKB
  • protein export from nucleus Source: Ensembl
  • regulation of anion transport Source: Ensembl
  • regulation of cardiac conduction Source: Reactome
  • regulation of ion transmembrane transporter activity Source: UniProtKB
  • regulation of mRNA 3'-end processing Source: UniProtKB
  • response to calcium ion Source: UniProtKB
  • S-adenosylmethionine cycle Source: GO_Central

Keywordsi

Molecular functionRNA-binding
Biological processOne-carbon metabolism
LigandNAD

Enzyme and pathway databases

ReactomeiR-HSA-112043. PLC beta mediated events.
R-HSA-1489509. DAG and IP3 signaling.
R-HSA-2029485. Role of phospholipids in phagocytosis.
R-HSA-2871809. FCERI mediated Ca+2 mobilization.
R-HSA-422356. Regulation of insulin secretion.
R-HSA-5218921. VEGFR2 mediated cell proliferation.
R-HSA-5578775. Ion homeostasis.
R-HSA-5607763. CLEC7A (Dectin-1) induces NFAT activation.
R-HSA-983695. Antigen activates B Cell Receptor (BCR) leading to generation of second messengers.
SIGNORiO43865.

Names & Taxonomyi

Protein namesi
Recommended name:
S-adenosylhomocysteine hydrolase-like protein 1Imported
Alternative name(s):
DC-expressed AHCY-like molecule
IP(3)Rs binding protein released with IP(3)
Short name:
IRBIT
Putative adenosylhomocysteinase 2
S-adenosyl-L-homocysteine hydrolase 2
Short name:
AdoHcyase 2
Gene namesi
Name:AHCYL1Imported
Synonyms:DCAL, IRBIT, XPVKONAImported
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

HGNCiHGNC:344. AHCYL1.

Subcellular locationi

  • Endoplasmic reticulum By similarity
  • Cytoplasmcytosol By similarity
  • Microsome By similarity
  • Apical cell membrane By similarity

  • Note: Associates with membranes when phosphorylated, probably through interaction with ITPR1.By similarity

GO - Cellular componenti

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Endoplasmic reticulum, Membrane, Microsome

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi52T → A: No effect on interaction with SLC4A4. 1 Publication1
Mutagenesisi58T → A: No effect on interaction with SLC4A4. 1 Publication1
Mutagenesisi62S → A: No effect on interaction with SLC4A4. No effect on interaction with FIP1L1. 2 Publications1
Mutagenesisi64S → A: No effect on interaction with ITPR1. No effect on phosphorylation. No effect on interaction with SLC4A4. No effect on interaction with FIP1L1. 3 Publications1
Mutagenesisi66S → A: Slightly decreases interaction with ITPR1. Slightly decreases phosphorylation. No effect on interaction with SLC4A4. Abolishes interaction with FIP1L1. 3 Publications1
Mutagenesisi68S → A: Abolishes interaction with ITPR1. Highly decreases phosphorylation. No effect on formation of multimers. Abolishes interaction with SLC4A4. Abolishes interaction with FIP1L1. Highly decreases interaction with SLC9A3. Highly decreases interaction with SLC9A3; when associated whith A-71 and A-74. 4 Publications1
Mutagenesisi70S → A: Highly decreases interaction with ITPR1. No effect on phosphorylation. No effect on interaction with SLC4A4. Abolishes interaction with FIP1L1. 3 Publications1
Mutagenesisi71S → A: Abolishes interaction with ITPR1. Highly decreases phosphorylation. Abolishes interaction with SLC4A4. Abolishes interaction with FIP1L1. Highly decreases interaction with SLC9A3; when associated whith A-68 and A-74. 4 Publications1
Mutagenesisi72T → A: Highly decreases interaction with ITPR1. Slightly increases phosphorylation. No effect on interaction with SLC4A4. Highly decreases interaction with FIP1L1. 3 Publications1
Mutagenesisi74S → G: Abolishes interaction with ITPR1. Slightly decreases phosphorylation. Strongly decreases interaction with SLC4A4. Abolishes interaction with FIP1L1. Highly decreases interaction with SLC9A3; when associated whith A-68 and A-71. 4 Publications1
Mutagenesisi76S → G: No effect on interaction with ITPR1. No effect on phosphorylation. No effect on interaction with SLC4A4. No effect on interaction with FIP1L1. 3 Publications1
Mutagenesisi77S → A: Highly decreases interaction with ITPR1. Slightly decreases phosphorylation. Strongly decreases interaction with SLC4A4. Abolishes interaction with FIP1L1. 3 Publications1
Mutagenesisi80S → A: No effect on interaction with SLC4A4. Highly decreases interaction with FIP1L1. 3 Publications1
Mutagenesisi82T → A: No effect on interaction with ITPR1. No effect on phosphorylation. No effect on interaction with SLC4A4. Decreases interaction with FIP1L1. 3 Publications1
Mutagenesisi84S → A: Slightly decreases interaction with ITPR1. No effect on phosphorylation. No effect on interaction with SLC4A4. Decreases interaction with FIP1L1. 3 Publications1
Mutagenesisi85S → A: Slightly decreases interaction with ITPR1. No effect on phosphorylation. No effect on interaction with SLC4A4. Decreases interaction with FIP1L1. 3 Publications1
Mutagenesisi90S → A: No effect on interaction with ITPR1. No effect on phosphorylation. No effect on interaction with SLC4A4. No effect on interaction with FIP1L1. 3 Publications1
Mutagenesisi97T → A: No effect on interaction with ITPR1. No effect on interaction with SLC4A4. No effect on interaction with FIP1L1. 3 Publications1

Organism-specific databases

DisGeNETi10768.
OpenTargetsiENSG00000168710.
PharmGKBiPA24637.

Chemistry databases

ChEMBLiCHEMBL3751646.

Polymorphism and mutation databases

BioMutaiAHCYL1.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedCombined sources
ChainiPRO_00001169082 – 530S-adenosylhomocysteine hydrolase-like protein 1Add BLAST529

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylserineCombined sources1
Modified residuei2PhosphoserineCombined sources1
Modified residuei40N6-acetyllysineBy similarity1
Modified residuei68Phosphoserine2 Publications1
Modified residuei71Phosphoserine2 Publications1
Modified residuei74Phosphoserine1 Publication1
Modified residuei77Phosphoserine1 Publication1
Modified residuei84PhosphoserineBy similarity1
Modified residuei391PhosphoserineCombined sources1
Isoform 2 (identifier: O43865-2)
Modified residuei1N-acetylmethionineCombined sources1

Post-translational modificationi

Phosphorylated at Ser/Thr residues between Ser-68 and Thr-72 in the PEST region: required for interaction with dATP-bound RRM1 and ITPR1. Phosphorylation at Ser-68 by PRKD1 and CAMK4 is required for further phosphorylations by CSNK1A1 (PubMed:16793548). Phosphorylation is induced by oxidative stress (PubMed:19224921). Probably phosphorylated by CAMK2A; phosphorylation at Ser-68 may be required for interaction with SLC9A3 (PubMed:20584908).1 Publication3 Publications

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiO43865.
MaxQBiO43865.
PaxDbiO43865.
PeptideAtlasiO43865.
PRIDEiO43865.

PTM databases

iPTMnetiO43865.
PhosphoSitePlusiO43865.

Miscellaneous databases

PMAP-CutDBiO43865.

Expressioni

Tissue specificityi

Expressed in dendritic cells.1 Publication

Developmental stagei

Expression increases markedly during activation of blood and skin DC (Langerhans cells), but is diminished in terminally differentiated tonsil DC.1 Publication

Gene expression databases

BgeeiENSG00000168710.
CleanExiHS_AHCYL1.
ExpressionAtlasiO43865. baseline and differential.
GenevisibleiO43865. HS.

Organism-specific databases

HPAiHPA042589.

Interactioni

Subunit structurei

Forms multimers (PubMed:16793548). Forms heteromultimers with AHCYL2 (via the C-terminal region) (PubMed:19220705). Interacts (when phosphorylated) with ITPR1 (when not phosphorylated); the interaction suppresses inositol 1,4,5-trisphosphate binding to ITPR1 (PubMed:16793548). Interacts with CFTR and SLC26A6; the interactions take place once AHCYL1 is released from ITPR1 and increase CFTR and SLC26A6 activities (By similarity). Interacts with RRM1; in a phosphorylation- and (dATP)-dependent manner. Interacts (via PEST domain when phosphorylated) with SLC4A4 isoform 1 but not isoform 2; the interaction increases SLC4A4 isoform 1 activity (PubMed:16769890). Interacts (when phosphorylated) with SLC9A3; the interaction is required for SLC9A3 apical location and activity (PubMed:18829453, PubMed:20584908). Interacts (when phosphorylated) with FIP1L1; the interaction is direct and associates AHCYL1 with the CPSF complex and RNA (PubMed:19224921). Interacts with PAPOLA (PubMed:19224921).By similarity7 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • identical protein binding Source: IntAct

Protein-protein interaction databases

BioGridi115987. 192 interactors.
IntActiO43865. 31 interactors.
STRINGi9606.ENSP00000358814.

Structurei

Secondary structure

1530
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi113 – 124Combined sources12
Helixi128 – 137Combined sources10
Turni142 – 145Combined sources4
Beta strandi147 – 152Combined sources6
Helixi156 – 167Combined sources12
Beta strandi171 – 175Combined sources5
Beta strandi177 – 180Combined sources4
Helixi184 – 193Combined sources10
Beta strandi196 – 198Combined sources3
Helixi205 – 216Combined sources12
Beta strandi224 – 231Combined sources8
Helixi232 – 240Combined sources9
Helixi242 – 245Combined sources4
Beta strandi249 – 253Combined sources5
Helixi256 – 265Combined sources10
Turni266 – 269Combined sources4
Beta strandi275 – 277Combined sources3
Helixi282 – 293Combined sources12
Helixi299 – 305Combined sources7
Beta strandi313 – 317Combined sources5
Helixi321 – 333Combined sources13
Beta strandi336 – 340Combined sources5
Helixi344 – 352Combined sources9
Helixi360 – 362Combined sources3
Turni363 – 366Combined sources4
Beta strandi368 – 372Combined sources5
Helixi382 – 387Combined sources6
Beta strandi392 – 396Combined sources5
Turni400 – 403Combined sources4
Helixi406 – 409Combined sources4
Beta strandi415 – 420Combined sources6
Beta strandi423 – 427Combined sources5
Beta strandi433 – 437Combined sources5
Helixi438 – 440Combined sources3
Helixi444 – 446Combined sources3
Helixi452 – 471Combined sources20
Beta strandi479 – 482Combined sources4
Helixi486 – 496Combined sources11
Helixi497 – 500Combined sources4
Helixi509 – 514Combined sources6
Beta strandi519 – 521Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
3MTGX-ray2.64A/B89-530[»]
ProteinModelPortaliO43865.
SMRiO43865.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiO43865.

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni65 – 92PEST1 PublicationAdd BLAST28
Regioni281 – 448NAD bindingBy similarityAdd BLAST168
Regioni520 – 530PDZ-bindingBy similarityAdd BLAST11

Domaini

The PEST region is essential for the interaction with ITPR1, and, when phosphorylated, is also the RRM1-binding region. The PDZ-binding region is required for maximal interaction with ITPR1 and is also responsible for the IP3-insensitive interaction with ITPR1 (By similarity).By similarity1 Publication

Sequence similaritiesi

Belongs to the adenosylhomocysteinase family.Curated

Phylogenomic databases

eggNOGiKOG1370. Eukaryota.
COG0499. LUCA.
GeneTreeiENSGT00390000003626.
HOGENOMiHOG000227986.
HOVERGENiHBG005041.
InParanoidiO43865.
KOiK01251.
OMAiPVKKQIQ.
OrthoDBiEOG091G06EB.
PhylomeDBiO43865.
TreeFamiTF300415.

Family and domain databases

CDDicd00401. SAHH. 1 hit.
InterProiView protein in InterPro
IPR000043. Adenosylhomocysteinase-like.
IPR015878. Ado_hCys_hydrolase_NAD-bd.
IPR016040. NAD(P)-bd_dom.
IPR020082. S-Ado-L-homoCys_hydrolase_CS.
PANTHERiPTHR23420. PTHR23420. 1 hit.
PfamiView protein in Pfam
PF05221. AdoHcyase. 1 hit.
PF00670. AdoHcyase_NAD. 1 hit.
PIRSFiPIRSF001109. Ad_hcy_hydrolase. 1 hit.
SMARTiView protein in SMART
SM00996. AdoHcyase. 1 hit.
SM00997. AdoHcyase_NAD. 1 hit.
SUPFAMiSSF51735. SSF51735. 1 hit.
TIGRFAMsiTIGR00936. ahcY. 1 hit.
PROSITEiView protein in PROSITE
PS00738. ADOHCYASE_1. 1 hit.
PS00739. ADOHCYASE_2. 1 hit.

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: O43865-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MSMPDAMPLP GVGEELKQAK EIEDAEKYSF MATVTKAPKK QIQFADDMQE
60 70 80 90 100
FTKFPTKTGR RSLSRSISQS STDSYSSAAS YTDSSDDEVS PREKQQTNSK
110 120 130 140 150
GSSNFCVKNI KQAEFGRREI EIAEQDMSAL ISLRKRAQGE KPLAGAKIVG
160 170 180 190 200
CTHITAQTAV LIETLCALGA QCRWSACNIY STQNEVAAAL AEAGVAVFAW
210 220 230 240 250
KGESEDDFWW CIDRCVNMDG WQANMILDDG GDLTHWVYKK YPNVFKKIRG
260 270 280 290 300
IVEESVTGVH RLYQLSKAGK LCVPAMNVND SVTKQKFDNL YCCRESILDG
310 320 330 340 350
LKRTTDVMFG GKQVVVCGYG EVGKGCCAAL KALGAIVYIT EIDPICALQA
360 370 380 390 400
CMDGFRVVKL NEVIRQVDVV ITCTGNKNVV TREHLDRMKN SCIVCNMGHS
410 420 430 440 450
NTEIDVTSLR TPELTWERVR SQVDHVIWPD GKRVVLLAEG RLLNLSCSTV
460 470 480 490 500
PTFVLSITAT TQALALIELY NAPEGRYKQD VYLLPKKMDE YVASLHLPSF
510 520 530
DAHLTELTDD QAKYLGLNKN GPFKPNYYRY
Length:530
Mass (Da):58,951
Last modified:April 4, 2006 - v2
Checksum:i974D23361A245D04
GO
Isoform 2 (identifier: O43865-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-47: Missing.

Note: Derived from EST data.Combined sources
Show »
Length:483
Mass (Da):53,753
Checksum:i18DFC7E74697E1D4
GO

Sequence cautioni

The sequence AAC01960 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
The sequence BI460083 differs from that shown. Reason: Frameshift at several positions.Curated
The sequence CAB43223 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti94K → M in T19009 (PubMed:7782076).Curated1
Sequence conflicti99S → F in T19009 (PubMed:7782076).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0217511 – 47Missing in isoform 2. 5 PublicationsAdd BLAST47

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF315687 mRNA. Translation: AAL26869.1.
AL036027 mRNA. No translation available.
AK303690 mRNA. Translation: BAG64680.1.
AK316110 mRNA. Translation: BAH14481.1.
AL049954 mRNA. Translation: CAB43223.2. Different initiation.
AL772411 Genomic DNA. Translation: CAH70965.1.
AL772411 Genomic DNA. Translation: CAH70966.1.
CH471122 Genomic DNA. Translation: EAW56426.1.
BC007576 mRNA. Translation: AAH07576.3.
BC010681 mRNA. Translation: AAH10681.3.
BC016942 mRNA. Translation: AAH16942.3.
BC065254 mRNA. Translation: AAH65254.2.
BC095476 mRNA. Translation: AAH95476.2.
BC110896 mRNA. Translation: AAI10897.2.
BI460083 mRNA. No translation available.
U82761 mRNA. Translation: AAC01960.1. Different initiation.
AU279527 mRNA. No translation available.
T19009 mRNA. No translation available.
BK005418 mRNA. Translation: DAA05763.1.
BK005417 mRNA. Translation: DAA05762.1.
CCDSiCCDS55620.1. [O43865-2]
CCDS818.1. [O43865-1]
PIRiT08681.
RefSeqiNP_001229602.1. NM_001242673.1. [O43865-2]
NP_001229603.1. NM_001242674.1. [O43865-2]
NP_001229604.1. NM_001242675.1. [O43865-2]
NP_001229605.1. NM_001242676.1. [O43865-2]
NP_006612.2. NM_006621.5. [O43865-1]
UniGeneiHs.743973.

Genome annotation databases

EnsembliENST00000359172; ENSP00000352092; ENSG00000168710. [O43865-2]
ENST00000369799; ENSP00000358814; ENSG00000168710. [O43865-1]
ENST00000393614; ENSP00000377238; ENSG00000168710. [O43865-2]
GeneIDi10768.
KEGGihsa:10768.
UCSCiuc001dyx.4. human. [O43865-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiSAHH2_HUMAN
AccessioniPrimary (citable) accession number: O43865
Secondary accession number(s): B4E168
, Q2TAJ6, Q502W8, Q5VSM0, Q6P171, Q96PK4, Q9UG84
Entry historyiIntegrated into UniProtKB/Swiss-Prot: December 15, 1998
Last sequence update: April 4, 2006
Last modified: August 30, 2017
This is version 168 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Caution

In spite of its similarity with AHCY, which catalyzes the reversible hydrolysis of S-adenosyl-L-homocysteine to adenosine and homocysteine, recombinant AHCYL1 expressed in bacteria shows no hydrolysase activity, nor does it affect the enzyme activity of AHCY.By similarity

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 1
    Human chromosome 1: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  4. SIMILARITY comments
    Index of protein domains and families