Q96HS1 (PGAM5_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Serine/threonine-protein phosphatase PGAM5, mitochondrial
EC=3.1.3.16

Alternative name(s):
Bcl-XL-binding protein v68
Phosphoglycerate mutase family member 5

Gene names

Name:

PGAM5

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	289 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Displays phosphatase activity for serine/threonine residues, and, dephosphorylates and activates MAP3K5 kinase. Has apparently no phosphoglycerate mutase activity. May be regulator of mitochondrial dynamics. Substrate for a KEAP1-dependent ubiquitin ligase complex. Contributes to the repression of NFE2L2-dependent gene expression. Acts as a central mediator for programmed necrosis induced by TNF, by reactive oxygen species and by calcium ionophore. Ref.5 Ref.6 Ref.10
Catalytic activity	A phosphoprotein + H2O = a protein + phosphate.
Subunit structure	Dimer. Forms a ternary complex with NFE2L2 and KEAP1. Interacts with BCL2L1 and MAP3K5. Upon TNF-induced necrosis, forms in complex with RIPK1, RIPK3 and MLKL; the formation of this complex leads to PGAM5 phosphorylation. Isoform 2, but not isoform 1, interacts with DNM1L; this interaction leads to DNM1L dephosphorylation and activation and eventually to mitochondria fragmentation. Ref.1 Ref.5 Ref.6 Ref.10
Subcellular location	Mitochondrion outer membrane; Single-pass membrane protein. Note: Isoform 2 overexpression results in the formation of disconnected punctuate mitochondria distributed throughout the cytoplasm. Isoform 1 overexpression results in the clustering of mitochondria around the nucleus. Ref.5
Domain	The N-terminal 35 amino acids, including the potential transmembrane alpha-helix, function as a non-cleaved mitochondrial targeting sequence that targets the protein to the cytosolic side of the outer mitochondrial membrane (Ref.5).
Post-translational modification	Both isoform 1 and isoform 2 are phosphorylated by the RIPK1/RIPK3 complex under necrotic conditions. This phosphorylation increases PGAM5 phosphatase activity.
Sequence similarities	Belongs to the phosphoglycerate mutase family. BPG-dependent PGAM subfamily.

Ontologies

Keywords
Biological process	Necrosis
Cellular component	Membrane Mitochondrion Mitochondrion outer membrane
Coding sequence diversity	Alternative splicing
Domain	Transmembrane Transmembrane helix
Molecular function	Hydrolase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Cellular_component	integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW mitochondrial outer membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	phosphoprotein phosphatase activity Inferred from electronic annotation. Source: EC
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q96HS1-1)

Also known as: PGAM5-L;

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.

Isoform 2 (identifier: Q96HS1-2)

Also known as: PGAM5-S;

The sequence of this isoform differs from the canonical sequence as follows:
     240-289: RALQFPPEGWLRLSLNNGSITHLVIRPNGRVALRTLGDTGFMPPDKITRS → SIPPLLSAGDFVLLGS

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 289

289

Serine/threonine-protein phosphatase PGAM5, mitochondrial

PRO_0000288782

Regions

Transmembrane

7 – 29

23

Helical; Potential

Region

77 – 82

6

Interaction with KEAP1

Amino acid modifications

Modified residue

80

1

Phosphoserine Ref.9

Modified residue

116

1

N6-acetyllysine Ref.7

Modified residue

144

1

N6-acetyllysine Ref.7

Modified residue

191

1

N6-acetyllysine Ref.7

Natural variations

Alternative sequence

240 – 289

50

RALQF…KITRS → SIPPLLSAGDFVLLGS in isoform 2.

VSP_025761

Experimental info

Mutagenesis

79

1

E → A: Loss of interaction with KEAP1; when associated with A-80. Ref.1

Mutagenesis

80

1

S → A: Loss of interaction with KEAP1; when associated with A-79. Ref.1

Mutagenesis

105

1

H → A: Loss of phosphatase activity. Ref.6

Sequence conflict

124

1

G → C in AAK60627. Ref.3

Isoform 2:

Sequence conflict

252

1

L → V in AAH08196. Ref.2

Secondary structure

1

.

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289

Helix Strand Turn

Details...

Beta strand

98 – 104

7

Helix

115 – 117

3

Helix

122 – 136

15

Beta strand

143 – 150

8

Helix

151 – 162

12

Beta strand

169 – 172

4

Helix

173 – 175

3

Helix

197 – 211

15

Beta strand

223 – 229

7

Helix

231 – 241

11

Helix

246 – 251

6

Beta strand

259 – 264

6

Beta strand

270 – 277

8

Helix

283 – 285

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (PGAM5-L) [UniParc]. Last modified May 29, 2007. Version 2. Checksum: EE20D2F0A99FCD83	FASTA	289	32,004
	10 20 30 40 50 60 MAFRQALQLA ACGLAGGSAA VLFSAVAVGK PRAGGDAEPR PAEPPAWAGG ARPGPGVWDP 70 80 90 100 110 120 NWDRREPLSL INVRKRNVES GEEELASKLD HYKAKATRHI FLIRHSQYHV DGSLEKDRTL 130 140 150 160 170 180 TPLGREQAEL TGLRLASLGL KFNKIVHSSM TRAIETTDII SRHLPGVCKV STDLLREGAP 190 200 210 220 230 240 IEPDPPVSHW KPEAVQYYED GARIEAAFRN YIHRADARQE EDSYEIFICH ANVIRYIVCR 250 260 270 280 ALQFPPEGWL RLSLNNGSIT HLVIRPNGRV ALRTLGDTGF MPPDKITRS
	Isoform 2 (PGAM5-S) [UniParc]. Checksum: 07B881D6D8BE033C	FASTA	255	28,020
	10 20 30 40 50 60 MAFRQALQLA ACGLAGGSAA VLFSAVAVGK PRAGGDAEPR PAEPPAWAGG ARPGPGVWDP 70 80 90 100 110 120 NWDRREPLSL INVRKRNVES GEEELASKLD HYKAKATRHI FLIRHSQYHV DGSLEKDRTL 130 140 150 160 170 180 TPLGREQAEL TGLRLASLGL KFNKIVHSSM TRAIETTDII SRHLPGVCKV STDLLREGAP 190 200 210 220 230 240 IEPDPPVSHW KPEAVQYYED GARIEAAFRN YIHRADARQE EDSYEIFICH ANVIRYIVCS 250 IPPLLSAGDF VLLGS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"PGAM5, a Bcl-XL-interacting protein, is a novel substrate for the redox-regulated Keap1-dependent ubiquitin ligase complex." Lo S.-C., Hannink M. J. Biol. Chem. 281:37893-37903(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], IDENTIFICATION BY MASS SPECTROMETRY, ALTERNATIVE SPLICING, SUBUNIT, INTERACTION WITH BCL2L1 AND KEAP1, MUTAGENESIS OF GLU-79 AND SER-80.
[2]	"The finished DNA sequence of human chromosome 12." Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R. , Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K., Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D., Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J., Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A., Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M., Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I., Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A., Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G., Gibbs R.A. Nature 440:346-351(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). Tissue: Cervix.
[4]	"In vitro selection and characterization of Bcl-X(L)-binding proteins from a mix of tissue-specific mRNA display libraries." Hammond P.W., Alpin J., Rise C.E., Wright M., Kreider B.L. J. Biol. Chem. 276:20898-20906(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 124-157. Tissue: Kidney.
[5]	"PGAM5 tethers a ternary complex containing Keap1 and Nrf2 to mitochondria." Lo S.-C., Hannink M. Exp. Cell Res. 314:1789-1803(2008) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY, SUBUNIT, INTERACTION WITH NFE2L2 AND KEAP1, FUNCTION, SUBCELLULAR LOCATION.
[6]	"Mitochondrial phosphoglycerate mutase 5 uses alternate catalytic activity as a protein serine/threonine phosphatase to activate ASK1." Takeda K., Komuro Y., Hayakawa T., Oguchi H., Ishida Y., Murakami S., Noguchi T., Kinoshita H., Sekine Y., Iemura S., Natsume T., Ichijo H. Proc. Natl. Acad. Sci. U.S.A. 106:12301-12305(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH MAP3K5, MUTAGENESIS OF HIS-105.
[7]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-116; LYS-144 AND LYS-191, MASS SPECTROMETRY.
[8]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[9]	"System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation." Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B. Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-80, MASS SPECTROMETRY.
[10]	"The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways." Wang Z., Jiang H., Chen S., Du F., Wang X. Cell 148:228-243(2012) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, IDENTIFICATION IN COMPLEX WITH RIPK1; RIPK3 AND MLKL, INTERACTION WITH DNM1L.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

EU249757 mRNA. Translation: ABX39494.1.
AC135586 Genomic DNA. No translation available.
BC008196 mRNA. Translation: AAH08196.1.
AF357523 mRNA. Translation: AAK60627.1.

IPI

IPI00063242.
IPI00788907.

RefSeq

NP_001164014.1. NM_001170543.1.
NP_612642.2. NM_138575.3.

UniGene

Hs.102558.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3MXO	X-ray	1.70	A/B	90-289	[»]
3O0T	X-ray	1.90	A/B	90-289	[»]

ProteinModelPortal

Q96HS1.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q96HS1. 22 interactions.

MINT

MINT-1385191.

PTM databases

PhosphoSite

Q96HS1.

Polymorphism databases

DMDM

150417955.

Proteomic databases

PaxDb

Q96HS1.

PRIDE

Q96HS1.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000317555; ENSP00000321503; ENSG00000247077.
ENST00000498926; ENSP00000438465; ENSG00000247077.

GeneID

192111.

KEGG

hsa:192111.

UCSC

uc001uku.3. human.
uc009zyv.3. human.

Organism-specific databases

CTD

192111.

GeneCards

GC12P133287.

H-InvDB

HIX0017319.

HGNC

HGNC:28763. PGAM5.

HPA

HPA036978.
HPA036979.

MIM

614939. gene.

neXtProt

NX_Q96HS1.

PharmGKB

PA143485574.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG71348.

HOGENOM

HOG000261217.

HOVERGEN

HBG105576.

InParanoid

Q96HS1.

KO

K15637.

OMA

WLRMSLN.

OrthoDB

EOG4T4CW2.

Gene expression databases

ArrayExpress

Q96HS1.

Bgee

Q96HS1.

CleanEx

HS_PGAM5.

Genevestigator

Q96HS1.

Family and domain databases

InterPro

IPR013078. His_Pase_superF_clade-1.
[Graphical view]

Pfam

PF00300. His_Phos_1. 1 hit.
[Graphical view]

SMART

SM00855. PGAM. 1 hit.
[Graphical view]

PROSITE

PS00175. PG_MUTASE. False negative.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

Q96HS1.

GenomeRNAi

192111.

NextBio

89319.

SOURCE

Search...

Entry information

Entry name

PGAM5_HUMAN

Accession

Primary (citable) accession number: Q96HS1
Secondary accession number(s): A9LN06, C9IZY7, Q96JB0

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 29, 2007
Last sequence update:	May 29, 2007
Last modified:	May 1, 2013
This is version 84 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.