MYO7A

MYO7A encodes unconventional myosin-VIIa, an actin-based molecular motor of the class VII myosins. It is built from an N-terminal motor (actin-activated ATPase) domain, a neck with five IQ motifs that bind calmodulin and CALML4 light chains, a single-alpha-helix lever-arm extension, and a long tail containing two MyTH4-FERM modules separated by an SH3 domain. Kinetically it is a slow, high-duty-ratio motor whose rate-limiting ADP release produces long-lived, strongly actin-bound states, suiting it to sustained force production and tension holding as well as slow cargo movement along F-actin; purified full-length molecules are largely monomeric and autoinhibited through a tail-motor interaction until cargo adaptors engage the tail. In cochlear and vestibular hair cells, myosin-VIIa is concentrated in the actin-filled stereocilia, where together with the scaffold proteins harmonin (USH1C) and sans (USH1G) it forms the upper tip-link density and pulls on cadherin-23 to maintain resting tension on the tip link, setting the operating point of the mechanoelectrical transduction apparatus; it also contributes to differentiation, morphogenesis and organization of the hair bundle. In the retinal pigment epithelium its tail binds the RAB27A effector MYRIP, coupling melanosomes to apical cortical actin and restraining their long-range movements, and the motor participates in the positioning and lysosomal processing of phagosomes derived from shed photoreceptor outer segments; a pool of the protein is tightly associated with the lysosome surface. In photoreceptor cells it is present in the inner segment, the base of the outer segment, the connecting cilium region and the synaptic ending, where, in part through the giant spectrin betaV scaffold, it contributes to opsin transport toward the outer segment and to outer-segment disk renewal. Loss of myosin-VIIa function in humans causes Usher syndrome type 1B, combining congenital profound sensorineural deafness, vestibular areflexia and progressive retinitis pigmentosa; other alleles cause nonsyndromic recessive (DFNB2) or dominant (DFNA11) hearing loss.

Disorders

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