MYO5A

MYO5A encodes myosin Va, an actin-based motor protein that transports intracellular organelle cargoes to the cell periphery and into specialized cellular processes (PMID:12897212, PMID:10749990). In melanocytes, MYO5A operates within a RAB27A/melanophilin (MLPH) receptor complex to drive peripheral accumulation of melanosomes; loss of function disrupts this distribution, and genetic epistasis across MYO5A, RAB27A, and MLPH places these three components in one transport pathway underlying Griscelli syndrome type 1, with a melanocyte-restricted F-exon required for pigment-cell function (PMID:12897212, PMID:15550542). Cargo recognition is mediated by the autonomously folded C-terminal globular tail domain, which binds organelles for transport: a dominant-negative fragment comprising only this domain competitively displaces smooth endoplasmic reticulum vesicles from Purkinje cell dendritic spines (PMID:10749990, PMID:24192353). In neurons, MYO5A is required for organelle transport and distribution within somatodendritic processes (PMID:29217155), and it links to early endosomal trafficking through a physical interaction with ANKFY1, an effector of RAB5A (PMID:40022605). Loss of MYO5A in the nervous system produces cerebellar developmental defects with expansion of PAX6-positive external granule layer cells, elongated mitochondria indicating disrupted mitochondrial homeostasis, and secondary neurochemical perturbations including hyperphosphorylation of alpha-synuclein and tau, DOPAL accumulation, and mitochondrial alpha-synuclein deposition with impaired respiratory complex I and IV activity (PMID:29217155, PMID:40022605). The motor's function is conserved across mammals, with loss-of-function truncating mutations phenocopying Griscelli syndrome type 1 (PMID:34680875).

1. 2000 High

   Established that the MYO5A C-terminal globular tail domain is the cargo-binding module by showing a fragment containing only this domain acts as a dominant negative against organelle delivery, defining how the motor engages cargo.

   Evidence Dominant-negative competition assay in flailer mice expressing a Gnb5-Myo5a hybrid, scoring SER vesicle localization to Purkinje cell dendritic spines

   PMID:10749990

   Open questions at the time

   • Did not resolve the molecular receptor on SER vesicles
   • Tail-cargo interaction inferred from competition, not direct binding
2. 2003 High

   Resolved how MYO5A recognizes melanosome cargo by placing it in a RAB27A/MLPH receptor complex and showing a melanocyte-restricted F-exon is required for pigment-cell function, explaining tissue specificity of Griscelli syndrome type 1.

   Evidence Genetic analysis of Griscelli patient mutations with epistasis across MYO5A, RAB27A, and MLPH

   PMID:12897212

   Open questions at the time

   • Structural basis of the tail-MLPH-RAB27A interface not defined
   • Mechanism of F-exon regulation of cargo binding unresolved
3. 2004 High

   Defined the cellular boundary of MYO5A function by showing it drives peripheral melanosome accumulation but is dispensable for melanosome transfer to keratinocytes, and placed the dsu suppressor in a parallel pathway.

   Evidence Dilute (Myo5a-deficient) mouse melanosome distribution analysis with dsu genetic epistasis

   PMID:15550542

   Open questions at the time

   • Molecular identity and mechanism of the dsu pathway not established here
   • Does not address neuronal cargo
4. 2013 Low

   Showed the globular tail domain is an autonomously folded, structurally tractable module, enabling structural study of cargo recognition.

   Evidence Expression, purification, crystallization, and 2.5 A diffraction of the human MYO5A globular tail

   PMID:24192353

   Open questions at the time

   • No structure solved or deposited in this report
   • No functional or cargo-bound complex structure
5. 2017 Medium

   Extended MYO5A function into neuronal organelle homeostasis by linking its loss to impaired somatodendritic organelle transport and downstream neurochemical pathology in dopaminergic neurons.

   Evidence Spontaneous recessive Myo5a mutant rats with biochemical assays for protein phosphorylation, aldehyde dehydrogenase activity, and mitochondrial respiratory complex activity

   PMID:29217155

   Open questions at the time

   • Alpha-synuclein/tau and DOPAL changes are secondary consequences with undefined causal chain
   • Single lab, single model
6. 2021 Medium

   Confirmed by independent loss-of-function models that reduced full-length MYO5A protein directly causes deficient melanosome transport, and that truncating MYO5A mutations phenocopy Griscelli syndrome type 1 across mammals.

   Evidence Loss-of-function mutant mice (genome/RNA sequencing, protein quantification, melanosome transport) and a Dachshund frameshift variant with co-segregation and histopathology

   PMID:33715225 PMID:34680875

   Open questions at the time

   • Does not add new molecular mechanism beyond confirming motor requirement
   • Conservation inferred phenotypically, not biochemically
7. 2025 Medium

   Connected MYO5A to early endosomal trafficking and mitochondrial homeostasis by identifying a direct MYO5A-ANKFY1 (RAB5A effector) interaction and showing cerebellar developmental and mitochondrial defects on MYO5A loss.

   Evidence Loss-of-function mutant mice with mass spectrometry of cerebellar extracts, PAX6 immunofluorescence, co-immunoprecipitation (MYO5A-ANKFY1), and primary neuron morphology

   PMID:40022605

   Open questions at the time

   • MYO5A-ANKFY1 interaction from single Co-IP, not reciprocally validated or reconstituted
   • Causal link between endosomal trafficking and mitochondrial elongation not established
   • Single lab, not yet replicated

• How MYO5A motor activity is coordinated and regulated across its distinct cargo systems (melanosomes, SER vesicles, early endosomes) and how cargo loss propagates to mitochondrial and neurochemical pathology remains unresolved.
• No cargo-bound structural model of the tail-receptor complexes
• Mechanism linking organelle transport defects to alpha-synuclein/tau pathology undefined
• Regulation of cargo selection between melanocyte and neuronal contexts unknown