myosin-6; unconventional myosin-6 (MYO6, KIAA0389)

Function: - myosins are actin-based motor molecules with ATPase activity - unconventional myosins serve in intracellular movements - myosin 6 is a reverse-direction motor protein that moves towards the minus-end of actin filaments - has slow rate of actin-activated ADP release due to weak ATP binding - functions in a variety of intracellular processes such as vesicular membrane trafficking & cell migration - required for structural integrity of the Golgi via the p53-dependent pro-survival pathway - appears to be involved in a very early step of clathrin- mediated endocytosis in polarized epithelial cells - may act as a regulator of F-actin dynamics - may play a role in transporting DAB2 from the plasma membrane to specific cellular targets - required for structural integrity of inner ear hair cells (putative) - phosphorylation in the motor domain, induced by EGF, results in translocation of MYO6 from the cell surface to membrane ruffles & affects F-actin dynamics - phosphorylated in vitro by p21- activated kinase (PAK) (putative) - binding to calmodulin through a unique insert, not found in other myosins, located in the neck region between the motor domain & the IQ domain appears to contribute to the directionality reversal - occurs only if the C-terminal lobe of calmodulin is occupied by Ca⁺² - interaction with F-actin/ACTN1 occurs only at the apical brush border domain of the proximal tubule cells (putative) - interacts with DAB2 in vitro, the C-terminal globular tail binds a C-terminal region of DAB2 - interacts with CFTR - forms a complex with CFTR & DAB2 in the apical membrane of epithelial cells - interacts with OPTN Structure: - homodimer - divided into three regions: - N-terminal motor (head) domain - neck domain consisting of a calmodulin-binding linker domain & a single IQ motif - C-terminal tail region with a coiled-coil & a unique globular domain required for interaction with other proteins - contains 1 IQ domain - contains 1 myosin head-like domain Compartment: - Golgi, trans-Golgi network membrane - nucleus, cytoplasm, perinuclear region - membrane, clathrin-coated pit - cell projection, ruffle membrane - also present in endocyctic vesicles, & membrane ruffles - translocates from membrane ruffles, endocytic vesicles & cytoplasm to Golgi, perinuclear membrane & nucleus through induction by p53 & p53-induced DNA damage - recruited into membrane ruffles from cell surface by EGF- stimulation - colocalizes with DAB2 in clathrin-coated pits/vesicles - colocalizes with OPTN at the Golgi complex & in vesicular structures close to the plasma membrane (putative) - isoform 3: - cytoplasmic vesicle, clathrin-coated vesicle membrane - isoform 4: - cytoplasmic vesicle, clathrin-coated vesicle membrane Alternative splicing: named isoforms=5 Expression: - expressed in most tissues examined including heart, brain, placenta, pancreas, spleen, thymus, prostate, testis, ovary, small intestine & colon - highest levels in brain, pancreas, testis & small intestine - also expressed in fetal brain & cochlea - isoform 1 & isoform 2, containing the small insert, & isoform 4, containing neither insert, are expressed in unpolarized epithelial cells Pathology: - defects in MYO6 are the cause of a) deafness autosomal dominant type 22 b) deafness autosomal recessive type 37 c) deafness sensorineural with hypertrophic cardiomyopathy

General

phosphoprotein unconventional myosin

Properties

SIZE: entity length = 1294 aa MW = 150 kD COMPARTMENT: cytoplasm nuclear membrane golgi MOTIF: Myosin head-like {1-759} MOTIF: ATP-binding site NAME: ATP-binding site SITE: 151-158 domain {273-317} Thr phosphorylation site {T405} actin-binding site SITE: 665-672 FOR-BINDING-OF: F-actin binding calmodulin {782-810} IQ motif {814-834} coiled coil {864-1023} glutamate-rich region {920-1027} MOTIF: glutamate residue (SEVERAL) Thr phosphorylation site {T1097} Thr phosphorylation site {T1100} OPTN interaction {1116-1118} Tyr phosphorylation site {Y1146}

Database Correlations

OMIM correlations UniProt Q9UM54 Pfam PF00063 Entrez Gene 4646 Kegg hsa:4646

References

UniProt :accession Q9UM54