CIBAR1

CIBAR1 (FAM92A1) is a homodimeric BAR domain protein that sculpts cellular membranes to support mitochondrial architecture and ciliogenesis (PMID:30404948, PMID:39043703). Its crystal structure reveals an antiparallel crescent-shaped homodimer whose concave surface carries positively charged residue clusters that bind phosphoinositide- and cardiolipin-containing membranes, drive lipid clustering, and induce high membrane curvature in vitro (PMID:39043703, PMID:40484380); dimerization is the functional prerequisite for this membrane-bending activity (PMID:34648955). At the mitochondrial inner membrane, CIBAR1 acts as a peripheral protein on the matrix side and is required for normal cristae ultrastructure and organelle bioenergetics (PMID:30404948, PMID:34648955). At the base of cilia, CIBAR1 binds the N-terminal region of CBY1 — an interaction in which the dimerization of both partners synergistically enhances mutual affinity — and this complex is required for ciliogenesis; a nonsense FAM92A variant that disrupts the complex abolishes CIBAR1 recruitment to CBY1 and impairs cilium formation (PMID:30395363, PMID:40484380). In vivo loss of CIBAR1 produces cell-type-dependent ciliary defects with randomized left-right asymmetry, exocrine pancreatic lesions, and impaired glucose tolerance (PMID:39622622). In sperm, CIBAR1 partners with CBY3 at the flagellar annulus to position it at the midpiece/principal-piece junction, with loss causing kinked flagella and male infertility (PMID:38197861). CIBAR1 can also support membrane recruitment of the Fuzzy-Inturned RabGEF complex [PMID:bio_10.1101_2025.03.27.645700].

1. 2016 Low

   An early association placed a CIBAR1 splice variant in a proliferative/tumor context, raising the question of whether the protein had a nuclear or cell-cycle role.

   Evidence Co-immunoprecipitation with PCNA plus migration, proliferation, colony formation, and xenograft assays in cervical carcinoma cells

   PMID:27798880

   Open questions at the time

   • Single Co-IP without reciprocal validation
   • No mechanistic pathway linking CIBAR1 to PCNA function
   • Splice-variant-specific; not reconciled with later membrane-remodeling biology
2. 2018 High

   Established CIBAR1 as a membrane-remodeling BAR protein at the mitochondrial inner membrane, defining its core biochemical activity and an organelle role.

   Evidence Subcellular fractionation, EM, in vitro membrane-tubulation assay, and loss-of-function cell lines

   PMID:30404948

   Open questions at the time

   • Molecular trigger for matrix-side recruitment not defined
   • Relationship between mitochondrial and ciliary pools unresolved
3. 2018 High

   Identified the CIBAR1–CBY1 complex at the ciliary base as essential for ciliogenesis, extending the protein's role beyond mitochondria.

   Evidence Reciprocal Co-IP, immunofluorescence colocalization, Fam92a-KO mouse, and human variant segregation

   PMID:30395363

   Open questions at the time

   • Did not resolve the structural basis of the CBY1 interaction
   • Mechanism connecting CBY1 binding to curvature generation unknown
4. 2021 Medium

   Confirmed that the dimer, not the monomer, is the functional unit for membrane bending, clarifying the quaternary requirement for activity.

   Evidence Recombinant expression, size-exclusion chromatography, and liposome membrane-bending assays using an NT* spidroin dimerization tag

   PMID:34648955

   Open questions at the time

   • In vitro only; physiological dimer regulation not addressed
   • Single lab
5. 2024 High

   Solved the BAR domain structure and defined the concave-surface residues mediating phosphoinositide/cardiolipin binding, providing the physical basis for curvature induction and linking the protein to neuronal function.

   Evidence Crystal structure, atomistic MD simulations, biochemical membrane-binding assays, and FAM92A1-KO mouse cognitive/neuronal phenotyping

   PMID:39043703

   Open questions at the time

   • How specific lipid recognition is tuned across mitochondrial vs ciliary membranes not resolved
   • Neuronal phenotype mechanism not traced to a specific membrane substrate
6. 2024 High

   Showed CIBAR1 partners with CBY3 at the sperm flagellar annulus, demonstrating a tissue-specific paralog complex controlling annulus positioning and fertility.

   Evidence Cby3-KO and ciBAR1-KO mouse models, colocalization, Co-IP, EM, and fertility assays

   PMID:38197861

   Open questions at the time

   • Determinants selecting CBY1 vs CBY3 partnership not defined
   • Molecular mechanism of annulus membrane positioning incomplete
7. 2024 High

   Defined the in vivo consequences of CIBAR1 loss across tissues, establishing a cell-type-dependent ciliogenesis role with developmental and metabolic outcomes.

   Evidence ciBAR1-KO mouse histology, glucose tolerance testing, cilia quantification, and MEF ciliary assays

   PMID:39622622

   Open questions at the time

   • Basis of cell-type-dependent ciliary requirement unexplained
   • Link between ciliary defect and glucose intolerance mechanism not established
8. 2025 High

   Resolved the structural basis of the CIBAR1–CBY1 interaction, showing the BAR domain binds the CBY1 N-terminus and that mutual dimerization synergistically strengthens affinity.

   Evidence 2.2 Å crystal structure, structure-guided mutagenesis, and in vitro lipid- and protein-binding/dimerization assays

   PMID:40484380

   Open questions at the time

   • Does not show how complex formation is coupled to membrane curvature at the ciliary base in vivo
   • Regulation of complex assembly timing unknown
9. 2025 Medium

   Connected CIBAR1's membrane-binding activity to downstream ciliary signaling machinery by showing it can recruit a RabGEF complex to membranes.

   Evidence In vitro reconstitution and protein-lipid interaction studies (preprint)

   PMID:bio_10.1101_2025.03.27.645700

   Open questions at the time

   • Preprint, single lab
   • ciBAR1-specific recruitment mechanism not detailed
   • Not validated in cells/in vivo

• How CIBAR1 is partitioned and regulated between its mitochondrial, ciliary-base, and flagellar pools — and what selects its lipid and protein partners in each context — remains unresolved.
• No mechanism for targeting to distinct membrane compartments
• No upstream regulator of CIBAR1 recruitment identified
• Functional integration of mitochondrial vs ciliary roles unknown