N-terminal splicing extensions of the human MYO1C gene fine-tune the kinetics of the three full-length myosin IC isoforms

Lilach Zattelman, Ronit Regev, Marko Ušaj, Patrick Y.A. Reinke, Sven Giese, Abraham O. Samson, Manuel H. Taft, Dietmar J. Manstein, Arnon Henn

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The MYO1C gene produces three alternatively spliced isoforms, differing only in their N-terminal regions (NTRs). These isoforms, which exhibit both specific and overlapping nuclear and cytoplasmic functions, have different expression levels and nuclear– cytoplasmic partitioning. To investigate the effect of NTR extensions on the enzymatic behavior of individual isoforms, we overexpressed and purified the three full-length human isoforms from suspension-adapted HEK cells. MYO1CC favored the actomyosin closed state (AMC), MYO1C16 populated the actomyosin open state (AMO) and AMC equally, and MYO1C35 favored the AMO state. Moreover, the full-length constructs isomerized before ADP release, which has not been observed previously in truncated MYO1CC constructs. Furthermore, global numerical simulation analysis predicted that MYO1C35 populated the actomyosinADP closed state (AMDC) 5-fold more than the actomyosinADP open state (AMDO) and to a greater degree than MYO1CC and MYO1C16 (4- and 2-fold, respectively). On the basis of a homology model of the 35-a-mino acid NTR of MYO1C35 (NTR35) docked to the X-ray structure of MYO1CC, we predicted that MYO1C35 NTR residue Arg-21 would engage in a specific interaction with post-relay helix residue Glu-469, which affects the mechanics of the myosin power stroke. In addition, we found that adding the NTR35 peptide to MYO1CC yielded a protein that transiently mimics MYO1C35 kinetic behavior. By contrast, NTR35, which harbors the R21G mutation, was unable to confer MYO1C35-like kinetic behavior. Thus, the NTRs affect the specific nucleotide-binding properties of MYO1C isoforms, adding to their kinetic diversity. We propose that this level of fine-tuning within MYO1C broadens its adaptability within cells.

Original languageEnglish
Pages (from-to)17804-17818
Number of pages15
JournalJournal of Biological Chemistry
Issue number43
StatePublished - 27 Oct 2017

Bibliographical note

Publisher Copyright:
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.


This work was supported by Marie Curie Career Integration Grant 1403705/11 and Grant 296/13 from the Israeli Scientific Foundation (to A. H.). This work also was supported by the Volkswagen Stiftung, Niedersächsisches Vorab, Joint Lower Saxony-Israeli Research Projects (Grant VWZN3012) (to A. H., M. H. T., and D. J. M.). The authors declare that they have no conflicts of interest with the contents of this article.

FundersFunder number
Israeli Scientific Foundation
Joint Lower Saxony-Israeli Research ProjectsVWZN3012
Niedersächsisches Vorab
Volkswagen Stiftung
Marie Curie Cancer Care1403705/11, 296/13


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