FAM91A1

FAM91A1 is a subunit of an endosome-to-trans-Golgi-network (TGN) trafficking module that operates downstream of the clathrin-associated AP-1 coat (PMID:39013469). It forms a stable complex with WDR11, in which WDR11 directly and specifically recognizes 'super acidic cluster' (SAC) sequences on cargo proteins; assembly of the WDR11-FAM91A1 complex and its SAC-binding activity are both required for correct trafficking of SAC-containing cargo from endosomes to the TGN (PMID:39013469). FAM91A1 also directly binds the pontocerebellar hypoplasia (PCH) gene product TBC1D23 through a conserved surface, adopting a Z-shaped interface, and cooperates with TBC1D23 to direct endosome-to-Golgi trafficking of the axonal-growth regulator KIAA0319L (PMID:37903274). Loss of FAM91A1 in zebrafish produces developmental defects mirroring those of TBC1D23 depletion, linking this trafficking activity to the neurodevelopmental pathology of PCH (PMID:37903274). The complex was originally detected in brain synaptosomes as part of the dysbindin (DTNBP1)-associated proteome, co-purifying with WDR11 (PMID:25198678).

1. 2014 Medium

   Established FAM91A1 as a physical component of a brain protein assembly, placing it within the dysbindin-associated proteome and linking it to WDR11 before any function was known.

   Evidence Immunopurification from BAC transgenic mouse brain P2 synaptosome fraction with mass spectrometry and co-IP verification

   PMID:25198678

   Open questions at the time

   • Functional role of the FAM91A1-WDR11 association not addressed
   • Significance of the dysbindin interaction in trafficking left unresolved
   • No structural or mechanistic detail of the complex
2. 2023 High

   Resolved how FAM91A1 contributes to neurodevelopment by showing it directly binds the PCH gene product TBC1D23 and cooperates in trafficking the axonal regulator KIAA0319L.

   Evidence Crystal structure of the FAM91A1-TBC1D23 complex, direct interaction assays, and zebrafish loss-of-function with developmental phenotype readout

   PMID:37903274

   Open questions at the time

   • Does not define how cargo specificity is achieved at the molecular level
   • Relationship between the TBC1D23 interaction and the WDR11 complex not integrated
3. 2024 High

   Defined the molecular mechanism of the WDR11-FAM91A1 complex as a cargo-recognition module acting downstream of AP-1, with WDR11 reading 'super acidic cluster' motifs to route cargo from endosomes to the TGN.

   Evidence Cryo-EM structure of the human WDR11-FAM91A1 complex, biochemical binding assays, and zebrafish loss-of-function assays

   PMID:39013469

   Open questions at the time

   • Catalytic or enzymatic role (if any) of FAM91A1 within the complex not established
   • Full cargo repertoire bearing SAC motifs not enumerated
   • How the AP-1 coat hands cargo to the WDR11-FAM91A1 complex mechanistically undefined

• How the WDR11-FAM91A1-TBC1D23 trafficking activities are coordinated into a single pathway, and the complete set of SAC-bearing cargoes whose mistrafficking drives pontocerebellar hypoplasia, remain to be defined.
• No unified model linking SAC recognition and TBC1D23-dependent KIAA0319L trafficking
• Causative human FAM91A1 mutations not reported in the corpus