Adaptor protein complex 5 (AP-5) and the SPG11-SPG15 coat-like machinery in endolysosomal retrograde trafficking and human disease: A review.

Adaptor protein complex 5 (AP-5) remains the least mechanistically defined member of the mammalian AP family. Recent structural and cell biological studies indicate that it operates within a distinct endolysosomal trafficking machinery together with SPG11 (spatacsin) and SPG15 (spastizin), rather than simply conforming to the canonical organization of other AP complexes. Current evidence supports a model in which AP-5 serves as an adaptor-like core, whereas SPG11-SPG15 form an outer-coat-like scaffold that contributes to membrane recruitment and remodeling during retrograde trafficking. AP-5 dysfunction impairs cargo retrieval and endolysosomal homeostasis and is strongly associated with hereditary spastic paraplegia and inherited retinal diseases. By contrast, cancer-related observations are heterogeneous and largely concern individual subunits rather than the intact complex. Key questions are still unresolved, including the molecular basis of cargo recognition, the possible contribution of clathrin to carrier formation, and the mechanisms governing carrier budding and scission. This review integrates recent structural, cell-biological, and disease-related evidence to define the distinctive organization of AP-5 and highlight the major gaps that continue to limit our understanding of its role in retrograde trafficking and human disease.