SRY (human, Q05066) curation notes

Started 2026-10-24. Inputs: UniProt Q05066, GOA (46 rows), the OpenScientist report
(SRY-deep-research-openscientist.md, treated as leads), and primary papers cached under
publications/.

Identity and architecture

• 204 aa, Y-linked, single HMG box (UniProt DNA_BIND 60..128). Two NLSs flank the box
  (61..77 and 130..136 in UniProt). Human SRY has no glutamine-rich C-terminal domain;
  the mouse protein does (see genes/mouse/Sry/Sry-notes.md).
• Cloned as the candidate TDF: PMID:1695712

Molecular function

• Sequence-specific minor-groove binding with a sharp bend: PMID:1425584;
  PMID:8265659;
  NMR bend 54 +/- 2 degrees, reduced to 41 degrees by M64I PMID:11563911.
• Li et al. reassessed M64I: in the full-length protein the tail restores bending and the
  defect is nuclear localization PMID:16762365. So bend angle versus localization is unresolved for this allele.
• Transactivation of the human SOX9 TES with SF1 in NT2/D1 cells, and patient alleles
  reduce it PMID:21412441.
• Repression: SRY bridges via KRAB-O to KAP1 PMID:19850934.
  Physiological repressed targets are not established (RSPO1 is proposed only).

Nuclear import

• Two NLS pathways, CaM (N-terminal) and importin-beta (C-terminal):
  PMID:12764225; PMID:15746192.
• Exportin-4 imports SRY PMID:19349578; shuttling variants V60L/I90M reduce SOX9
  activation ~2-fold PMID:24003159.
• Acetylation K136 by p300 promotes import; HDAC3 deacetylation gives cytoplasmic SRY
  PMID:15297880.

Speckles / splicing

• Ohe et al. saw SRY in SC-35 speckles in NT2/D1 PMID:11818535; Knower et al. did not
  PMID:21412441.
  Nuclear speck is kept as non-core and contested; no splicing GO term proposed.

Disease (verified against cached abstracts)

• 46,XY complete gonadal dysgenesis (Swyer syndrome): de novo HMG-box mutations
  PMID:2247149; nonsense W->stop and G->R
  PMID:1339396; missense plus a frameshift deletion in 3/5 CGD patients PMID:1415266;
  five of 22 pure gonadal dysgenesis females had HMG-box changes, some de novo, one
  nonsense in sibs implying paternal gonadal mosaicism PMID:8353496.
• Inherited variants shared with fertile fathers (V60L, I90M) [PMID:24003159, PMID:2247149].
• Partial gonadal dysgenesis: S18N outside the HMG box, familial PMID:9521592.
• 46,XY ovotesticular presentation from a postzygotic gonadal SRY mutation (L101H)
  PMID:8447323.
• NLS variants (R62G, R75N, R76P, R133W) partly cytoplasmic PMID:12764225; R75M
  cytoplasmic in a 46,XY CGD female with dysgerminoma PMID:28030592.
• 46,XX testicular DSD: about 80% SRY-positive PMID:20301589, usually Xp;Yp
  translocation [PMID:25169080, PMID:32882067]. 46,XX ovotesticular cases with Yp on Xq
  PMID:10602113 or gonad-restricted SRY mosaicism PMID:9652903.

Annotation judgements (summary)

• Generic DNA binding (IDA, IEA) -> MODIFY to DNA binding, bending plus RNA pol II
  cis-regulatory region sequence-specific DNA binding.
• Protein binding to NHERF2/SIP-1 -> MODIFY to PDZ domain binding (C-terminal 7 aa of SRY
  bind the PDZ domains) PMID:9054412.
• DNA-binding TF binding (11 IPI rows, PMID:16582099): GST pulldowns of SRY HMG fragments
  with neural/glial TFs; real biochemistry, no SRY physiology -> KEEP_AS_NON_CORE.
• positive regulation of gene expression (NWD1, HEK293T overexpression, PMID:24681825) and
  positive regulation of DNA-templated transcription (PMID:21412441) -> MODIFY to positive
  regulation of transcription by RNA polymerase II.
• cell differentiation IBA -> MODIFY to Sertoli cell differentiation.
• NEW: calmodulin binding (PMID:15746192; mouse Sry also binds CaM, PMID:21558314).

Open questions

• Direct in vivo target set of human SRY (only SOX9 TES/Enh13 and FGF9 promoter proposed).
• Contribution of DNA bending versus nuclear dose to individual patient alleles.
• Extragonadal (dopaminergic neuron) role: human SRY in TH+ neurons PMID:22568433.