Identification and characterization of SSTK, a serine/threonine protein kinase essential for male fertility.
Here we describe and characterize a small serine/threonine kinase (SSTK) which consists solely of the N- and C-lobes of a protein kinase catalytic domain. SSTK protein is highly conserved among mammals, and no close homologues were found in the genomes of nonmammalian organisms. SSTK specifically interacts with HSP90-1beta, HSC70, and HSP70 proteins, and this association appears to be required for SSTK kinase activity. The SSTK transcript was most abundant in human and mouse testes but was also detected in all human tissues tested. In the mouse testis, SSTK protein was localized to the heads of elongating spermatids. Targeted deletion of the SSTK gene in mice resulted in male sterility due to profound impairment in motility and morphology of spermatozoa. A defect in DNA condensation in SSTK null mutants occurred in elongating spermatids at a step in spermiogenesis coincident with chromatin displacement of histones by transition proteins. SSTK phosphorylated histones H1, H2A, H2AX, and H3 but not H2B or H4 or transition protein 1 in vitro. These results demonstrate that SSTK is required for proper postmeiotic chromatin remodeling and male fertility. Abnormal sperm chromatin condensation is common in sterile men, and our results may provide insight into the molecular mechanisms underlying certain human infertility disorders.
Spiridonov
Nikolay A
NA
Division of Therapeutic Proteins, Center for Drug Evaluation and Research, Food and Drug Administration, HFD-122, Bldg. 29A, Rm. 3B-20, 8800 Rockville Pike, Bethesda, Maryland 20892, USA. spiridonov@cber.fda.gov
Wong
Lily
L
Zerfas
Patricia M
PM
Starost
Matthew F
MF
Pack
Svetlana D
SD
Paweletz
Cloud P
CP
Johnson
Gibbes R
GR
D000595:Amino Acid Sequence; D000818:Animals; D002384:Catalysis; D005298:Fertility / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D020869:Gene Expression Profiling; D050883:HSC70 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007248:Infertility, Male / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D013094:Spermatozoa / Q000378:metabolism / Q000473:pathology; D013379:Substrate Specificity; D013737:Testis / Q000378:metabolism / Q000473:pathology
D050883:HSC70 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; C493165:HSP90AB1 protein, human; C494371:HSPA8 protein, human; C494372:Hspa8 protein, mouse; D046912:Multiprotein Complexes; D012333:RNA, Messenger; C081884:heat-shock protein 70.1; D017346:Protein Serine-Threonine Kinases; C501082:TSSK6 protein, human; C501083:Tssk6 protein, mouse