ACRBP

ACRBP (SP32/OY-TES-1/CT23) is an acrosomal matrix protein that controls the packaging and timed activation of the sperm protease proacrosin during spermiogenesis and fertilization (PMID:8144514, PMID:27303034). It was first purified as a proacrosin-binding protein that selectively recognizes the 55-/53-/49-kDa proacrosin and acrosin-intermediate forms and accelerates proacrosin autoactivation at basic pH in vitro, acting through both amino- and carboxyl-terminal sequences of proacrosin (PMID:8144514). In mouse, alternative splicing generates two functionally distinct isoforms that bind separate domains of the proacrosin C-terminus: ACRBP-V5 drives formation and configuration of the large acrosomal granule during early spermiogenesis, while the processed ACRBP-C retains proacrosin in an inactive state and accelerates its autoactivation upon acrosomal exocytosis (PMID:23426433, PMID:27303034). Genetic ablation of both isoforms causes acrosome malformation, fragmented acrosomes, and severe subfertility, with ACRBP-V5 transgenic rescue restoring acrosomal granule formation; the subfertility reflects an incomplete acrosome reaction rather than impaired sperm migration (PMID:27303034, PMID:30606959). Maturation of ACRBP from precursor to mature form depends on the proprotein convertase PCSK4, and ACRBP undergoes tyrosine phosphorylation during capacitation, with surface ACRBP contributing to sperm–zona pellucida binding and priming of the acrosome reaction (PMID:22357636, PMID:15955892, PMID:34086710). A separate body of low-confidence work links ACRBP/OY-TES-1/CT23 knockdown to proliferation, migration, and apoptosis phenotypes in mesenchymal stem cells and hepatocellular carcinoma lines, but this somatic role has not been mechanistically resolved in the available corpus.

1. 1994 High

   Established the founding biochemical activity of ACRBP: it is a dedicated proacrosin-binding protein that physically engages proacrosin and controls its maturation kinetics.

   Evidence Protein purification from porcine sperm, in vitro binding assays, and proacrosin autoactivation assays with cDNA-based structural analysis

   PMID:8144514

   Open questions at the time

   • Did not define the structural basis of binding or distinguish whether acceleration occurs in vivo
   • Performed in porcine sperm without genetic confirmation of physiological role
2. 2005 High

   Linked ACRBP to capacitation signaling by showing it is a capacitation-specific tyrosine phosphorylation target whose acrosomal labeling is lost upon the acrosome reaction.

   Evidence 2D Western blot, mass spectrometry identification, reciprocal immunoprecipitation, and immunofluorescence in pig sperm

   PMID:15955892

   Open questions at the time

   • Kinase responsible not identified
   • Functional consequence of phosphorylation for proacrosin binding not tested
3. 2012 Medium

   Placed ACRBP maturation within a proteolytic processing pathway by identifying PCSK4 as required for conversion of the ACRBP precursor to its mature form.

   Evidence 2D differential in-gel electrophoresis, Western blot, and immunolocalization in PCSK4-knockout mice

   PMID:22357636

   Open questions at the time

   • Direct versus indirect PCSK4 substrate relationship unresolved
   • Did not isolate the contribution of ACRBP processing from other PCSK4 substrates in the phenotype
4. 2013 High

   Resolved that ACRBP acts through two alternatively spliced isoforms binding distinct proacrosin domains, separating granule-formation from autoactivation-control functions.

   Evidence GST pull-down, in vitro proacrosin autoactivation assay, immunolocalization, RT-PCR, and Western blot in mouse

   PMID:23426433

   Open questions at the time

   • Did not establish in vivo necessity of each isoform
   • Mechanism of differential domain selection not structurally defined
5. 2016 High

   Provided genetic proof of isoform-specific function: ACRBP-V5 is required for acrosomal granule formation, while ACRBP-W retains proacrosin inactive until exocytosis.

   Evidence ACRBP-knockout mice with ACRBP-V5 transgenic rescue, fertility and acrosome morphology assays, and proacrosin autoactivation assays

   PMID:27303034

   Open questions at the time

   • Did not define how ACRBP-V5 shapes granule architecture
   • Molecular trigger releasing proacrosin from ACRBP-W at exocytosis not identified
6. 2018 Medium

   Attributed ACRBP-null subfertility specifically to an incomplete acrosome reaction rather than defective sperm transport.

   Evidence In vivo sperm tracking in the female reproductive tract, motility, and morphology analysis in knockout mice

   PMID:30606959

   Open questions at the time

   • Did not quantify the acrosome reaction step that fails
   • Single-lab knockout phenotype without orthogonal model
7. 2021 Medium

   Extended ACRBP function to the sperm surface, implicating it in zona pellucida binding and priming the acrosome reaction.

   Evidence Antibody inhibition during IVF, sperm-ZP binding and acrosome reaction assays with solubilized ZP and SERCA inhibition in boar sperm

   PMID:34086710

   Open questions at the time

   • Surface ACRBP binding partner on the sperm or ZP not identified
   • Relationship between surface and matrix pools of ACRBP unclear
8. 2021 Low

   Reported a somatic role for ACRBP/OY-TES-1/CT23 in tumor and stem cell proliferation, migration, and apoptosis, including transcriptional regulation of MT1.

   Evidence RNAi/siRNA knockdown with proliferation, cycle, apoptosis, and migration assays plus microarray and Western blot in MSCs and HCC lines

   PMID:22651134 PMID:26339343 PMID:33559934

   Open questions at the time

   • Correlative knockdown phenotypes without a defined molecular mechanism for ACRBP
   • Direct biochemical link between ACRBP and MT1 not established
   • No reconciliation with the acrosomal proacrosin-binding function

• How tyrosine phosphorylation, PCSK4 processing, and the acrosome-reaction trigger are coordinated to time proacrosin release, and whether the somatic cancer-cell phenotypes reflect a genuine non-reproductive function, remain unresolved.
• No structure of the ACRBP-proacrosin complex
• Mechanism of proacrosin release at exocytosis undefined
• Somatic function lacks molecular mechanism