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PMID:20829357

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Citation

Jha, KN, Wong, L, Zerfas, PM, De Silva, RS, Fan, YX, Spiridonov, NA and Johnson, GR (2010) Identification of a novel HSP70-binding cochaperone critical to HSP90-mediated activation of small serine/threonine kinase. J. Biol. Chem. 285:35180-7

Abstract

We previously reported the identification of small serine/threonine kinase (SSTK) that is expressed in postmeiotic germ cells, associates with HSP90, and is indispensable for male fertility. Sperm from SSTK-null mice cannot fertilize eggs in vitro and are incapable of fusing with eggs that lack zona pellucida. Here, using the yeast two-hybrid screen, we have discovered a novel SSTK-interacting protein (SIP) that is expressed exclusively in testis. The gene encoding SIP is restricted to mammals and encodes a 125-amino acid polypeptide with a predicted tetratricopeptide repeat domain. SIP is co-localized with SSTK in the cytoplasm of spermatids as they undergo restructuring and chromatin condensation, but unlike SSTK, is not retained in the mature sperm. SIP binds to SSTK with high affinity (K(d) ∼10 nM), and the proteins associate with each other when co-expressed in cells. In vitro, SIP inhibited SSTK kinase activity, whereas the presence of SIP in cells resulted in enzymatic activation of SSTK without affecting Akt or MAPK activity. SIP was found to be associated with cellular HSP70, and analyses with purified proteins revealed that SIP directly bound HSP70. Importantly, SSTK recruited SIP onto HSP90, and treatment of cells with the specific HSP90 inhibitor, 17-allylamino-17-demethoxygeldanamycin, completely abolished SSTK catalytic activity. Hence, these findings demonstrate that HSP90 is essential for functional maturation of the kinase and identify SIP as a cochaperone that is critical to the HSP90-mediated activation of SSTK.

Links

PubMed PMC2966131 Online version:10.1074/jbc.M110.134767

Keywords

Animals; Base Sequence; Benzoquinones/pharmacology; Calcium-Binding Proteins/genetics; Calcium-Binding Proteins/metabolism; Enzyme Activation/genetics; Gene Expression Regulation, Enzymologic; HSP70 Heat-Shock Proteins/genetics; HSP70 Heat-Shock Proteins/metabolism; HSP90 Heat-Shock Proteins/antagonists & inhibitors; HSP90 Heat-Shock Proteins/genetics; HSP90 Heat-Shock Proteins/metabolism; Lactams, Macrocyclic/pharmacology; Male; Mice; Mice, Mutant Strains; Molecular Sequence Data; Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism; Spermatozoa/metabolism; Testis/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:TSACC

enables

GO:0051087: chaperone binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9BXA6

F

Seeded From UniProt

complete

HUMAN:TSSK6

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q96A04

F

Seeded From UniProt

complete

MOUSE:TSACC

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(EMAPA:17972)
  • part_of:(CL:0000018)

Seeded From UniProt

complete


See also

References

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