Disease relevance of MYO9B

• Inconsistent results concerning the association of polymorphisms in the MYO9B gene with celiac disease (CD) have been recently published [1].
• These findings suggested the current study investigating a possible further role for MYO9B variation in inflammatory bowel disease [2].
• Unlike previous variants (in other genes) reported to predispose to inflammatory bowel disease, the association at MYO9B was considerably stronger with ulcerative colitis, although weaker association with Crohn's disease also was observed [2].
• To address this, we performed an association study of a Norwegian IBD cohort (149 patients with Crohn's disease, 308 patients with ulcerative colitis and 562 healthy controls) using SNPs, which tagged the celiac disease associated MYO9B haplotype [3].
• Using an assay that studies the release of transport vesicles from the TGN in vitro, we provide functional evidence that p200/myosin is involved in the assembly of basolateral transport vesicles carrying vesicular stomatitis virus G protein (VSVG) from the TGN of polarized MDCK cells [4].

Psychiatry related information on MYO9B

• From these and other data, we conclude that the essential role(s) of myosin I in A. nidulans is probably structural, requiring little, if any, actin-activated MgATPase or motor activity, which have long been considered the defining characteristics of the myosin family [5].
• Cardiac myosin binding protein C gene is specifically expressed in heart during murine and human development [6].
• After exercise, the recovery of phosphocreatine-an index of oxidative metabolic capacity of the muscle-was slower in the beta myosin heavy chain group (mean half time 0.65 (0.08) minutes) than in the troponin T group (0.60 (0.17) minutes) or controls (0.48 (0.14) minutes) [7].
• In hyperthyroidism, the cross-bridge movement significantly preceded tension development, suggesting that hyperthyroid myosin (V1) has a longer latency period between the shift to the vicinity of the thin filament and force development [8].
• Newly-reported structural information about certain proximities between points on bound nucleotide and points on the heavy chain of myosin S-1 are incorporated into a previously-reported [Botts, J. Thomason, J.F. & Morales, M.F. Proc. Nat. Acad. Sci. USA, 86, 2204-2208 (1989)] structure of S-1 [9].

High impact information on MYO9B

• Kinetics shows that the binding of myosin to actin is a two-step process which affects ATP and ADP affinity [10].
• Molecular genetics of myosin [11].
• Structural and biochemical studies suggest that the position of tropomyosin (Tm) and troponin (Tn) on the thin filament determines the interaction of myosin with the binding sites on actin [12].
• 3) The initial rate of force development depends mostly on the extent of Ca(2+) activation of the thin filament and myosin kinetic properties but depends little on the initial force level [12].
• Second, the technology to measure picoNewton forces and nanometer distances has provided direct determinations of the force and step length generated by a single myosin molecule interacting with a single actin filament [13].

Chemical compound and disease context of MYO9B

• DESIGN AND METHODS: Serum myosin heavy-chain fragments, TnT, and TnI were studied up to 12 days after diagnosis in relationship to the serum creatine kinase level in 20 patients with rhabdomyolysis [14].
• METHODS AND RESULTS: Syngeneic splenocytes, coupled with cardiac myosin by use of ethylene carbodiimide, were administered intravenously before disease induction, and the effects of this peripheral tolerization on myosin-induced myocarditis were assessed [15].
• Compounds interfering with actin function, including phalloidin, the catalytic subunit of Clostridium botulinum C2 toxin, and N-ethylmaleimide-treated myosin S1 fragments were microinjected into the axon [16].
• The presence of ventricular myosin light chains in the atria of children with congenital heart disease was demonstrated by two-dimensional polyacrylamide gel electrophoresis, peptide mapping, and Western blot analysis [17].
• All Lewis rats immunized with the rod exhibited severe myocarditis, and the immunization of the cyanogen bromide-cleaved peptide equivalent to human beta-cardiac myosin heavy chain RDCB9 (residues 1070 to 1165) induced moderate myocarditis [18].

Biological context of MYO9B

• The family study revealed no distorted transmission of the aforementioned MYO9B polymorphisms or haplotypes [1].
• There is enough freedom for the myosin head to find the next location of the binding site along with the actin filament before complete dissociation from the filament [19].
• We found that myosin IXb has a rate-limiting ATP hydrolysis step unlike other known myosins, thus populating the prehydrolysis intermediate (M.ATP) [19].
• The heavy chains of the class IX myosins, rat myr5 and human myosin-IXb, contain within their tail domains a region with sequence homology to GTPase activating proteins for the rho family of G proteins [20].
• Physical mapping of human myosin-IXB (MYO9B), the human orthologue of the rat myosin myr 5, to chromosome 19p13.1 [21].

Anatomical context of MYO9B

• Here we report significant and replicable association (P = 2.1 x 10(-6)) to a common variant located in intron 28 of the gene myosin IXB (MYO9B), which encodes an unconventional myosin molecule that has a role in actin remodeling of epithelial enterocytes [22].
• Additionally, S2 possesses a conserved charge distribution with three prominent rings of negative potential within S2-Delta, the first of which may provide a binding interface for the "blocked head" of smooth muscle myosin in the OFF state [23].
• The observation that many disease-associated mutations affect the second negatively charged ring further suggests that charge interactions play an important role in regulation of cardiac muscle activity through myosin-binding protein C [23].
• In comparison to skeletal muscle myosin-II, the myosin-IXb 'head' has two unusual features: a novel N-terminal domain of 140 amino acids, which includes a 60 amino acid extension, and a large insertion of 126 amino acids in the putative actin-binding site [24].
• In this report we have examined the light chain content, actin binding properties, in vitro motility and rho-GTPase activity of human myosin-IXb purified from leukocytes [20].

Associations of MYO9B with chemical compounds

• Myosin light chain kinase functions downstream of Ras/ERK to promote migration of urokinase-type plasminogen activator-stimulated cells in an integrin-selective manner [25].
• The gelation induced by warming (to 25 degrees C) the 100,000 g supernatant fraction (extract) of HeLa cells lysed in a buffer containing sucrose, ATP, DTE, EGTA, imidazole, and Triton X-100 was studied in the presence of myosin and heavy meromyosin (HMM) [26].
• Using nondenaturing polyacrylamide gel electrophoresis, we have identified two distinct myosin isoenzymes in human atrial tissue that correspond to the V1 and V3 isomyosins found in rat ventricular tissue [27].
• The 3.1-A x-ray structure of the scallop myosin head domain (subfragment 1) in the ADP-bound near-rigor state (lever arm =45 degrees to the helical actin axis) shows the diphosphate moiety positioned on the surface of the nucleotide-binding pocket, rather than deep within it as had been observed previously [28].
• Fluorescently labeled turkey gizzard smooth muscle myosin was prepared by removal of endogenous regulatory light chain and re-addition of the light chain labeled at cysteine-108 with the 6-isomer of iodoacetamidotetramethylrhodamine (6-IATR) [29].

Other interactions of MYO9B

• Like myosin-Va, the velocity of myosin-IXb remains constant (38.2 +/- 1.2 nm/s) even at single motor/filament densities [30].
• No evidence of association of the MYO9B polymorphisms with celiac disease in the Spanish population [1].
• Human myosin-IXb, an unconventional myosin with a chimerin-like rho/rac GTPase-activating protein domain in its tail [24].
• Here we show that the putative TGN coat protein p200 (Narula, N., I. McMorrow, G. Plopper, J. Doherty, K.S. Matlin, B. Burke, and J.L. Stow. 1992. J. Cell Biol. 114: 1113-1124) is myosin II [4].
• MYO9B is a Rho family GTPase activating protein involved in epithelial cell cytoskeletal organisation [31].

Analytical, diagnostic and therapeutic context of MYO9B

• Northern blot analysis of 16 different human tissues revealed an approximately 8 kb transcript that is most highly expressed in peripheral blood leukocytes, with somewhat lower levels of expression in thymus and spleen, suggesting that myosin-IXb is most abundant in cells of myeloid origin [24].
• Myosin heavy chain isoforms were isolated and analysed by SDS-PAGE gel electrophoresis [32].
• Results: Common variation in MYO9B was associated with susceptibility to inflammatory bowel disease in all 3 cohorts examined (most associated SNP, rs1545620; meta-analysis P = 1.9 x 10(-6); odds ratio, 1.2), with the same alleles showing association as reported for celiac disease [2].
• The distribution of intracellular myosin was studied by the double antibody immunofluorescence method in primary organotypic neuronal cultures and two established neuronal and glial cell lines [33].
• The morphogenesis of myosin II structures in active lamella undergoing net protrusion was analyzed by correlative fluorescence and electron microscopy [34].

References