Disordered Motifs and Domains in Cell Control - October 11-15, 2014

Disordered Motifs and Domains in Cell Control

Poster Session II

33-POS Board 9 The Regulation of Non Muscle Myosin II by the Disordered Non-helical Tailpiece Noa Lahav 1 , Shoshana Ravid 2 , Assaf Friedler 1 . 1 The Hebrew university, Jerusalem, Israel, 2 The Hebrew university-Hadassah Medical School, Jerusalem, Israel. Non-muscle myosin II (NMII) mediates cellular processes that require contractility. It is composed of a globular motor domain in its N-terminal region and a coiled-coil rod domain in the C-terminal region and undergoes dynamic filament assembly-disassembly cycles to facilitate its activities. NMII isoform C (NMII-C) has a disordered 55-residue C-terminal tailpiece (residues 1946-2000), which regulates the filament assembly of NMII-C. The N-terminal region of the tailpiece (residues 1946-1967) has a net positive charge of +7 while its C-terminal region (residues 1968-2000) has a net negative charge of -10. We previously demonstrated that a peptide corresponding to the positive part of the non-helical tailpiece promotes filament assembly of NMII-C. Phosphorylation of two specific threonine residues (positions 1957 and 1960) in the positively charged region of the tailpiece introduces negative charges with consequent shift from attraction between NMII-C rods that leads to filament assembly, to repulsion leading to inhibition of filament assembly. We synthesized phosphorylated peptides derived from the positively charged region of the tailpiece, in which the relevant threonines were replaced by phosphothreonines. We found that a single phosphorylation on either of the two threonines resulted in inhibition of NMII-C 1296-1854 filament assembly. The positively charged tailpiece 1946-1967 and its derivatives modulate the filament assemble of NMII-C and thus may serve as lead compounds against diseases resulting from mutations that disrupt the NMII filament assembly such as cancer. Refernces: (1) Ronen, D., & Ravid, S. (2009), J Biol Chem, 284(37), 24948–24957. (2) Ronen, D., Rosenberg, M. M., Shalev, D. E., Rosenberg, M., Rotem, S., Friedler, A., & Ravid, S. (2010), J Biol Chem, 285(10), 7079–7086. (3) Rosenberg, M. M., Ronen, D., Lahav, N., Nazirov, E., Ravid, S., & Friedler, A. (2013), J Biol Chem, 288(14), 9779–89.

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