Our goal is to determine the molecular mechanisms of the myosin-I family of molecular motors. Myosin-Is comprise the largest unconventional myosin family found in humans (eight genes), and its large size and expression profile distinguish it as one of the most diverse. Myosin-Is physically link cell membranes to the underlying actin cytoskeleton where they play essential roles in powering membrane dynamics, membrane trafficking, and mechanical signal- transduction. Myosin-I's show remarkable diversity in their cellular function, which is mediated by their diverse biophysical properties, which includes dynamic tension sensing, membrane- attachment, and unique regulatory modes. Our goal is to provide the biochemical and biophysical foundation for understanding the molecular physiology of this important class of motors. We will use a combination of innovative biophysical techniques to define (1) the structural origin of myosin-I force sensing, (2) the role f myosin-I adaptor proteins in controlling myosin-I activity, and (3) control of myosin-I function by actin regulatory proteins.

Public Health Relevance

Myosin-Is are molecular motors that are expressed in nearly all eukaryotic cells. They are crucial for several normal and pathological processes, including: cell and tissue development, endocytosis, wound healing, hearing, and cell movement. However, the molecular details of myosin-I function in these crucial processes are unknown. Therefore, we will define the basic biochemical and biophysical properties of these motors to better understand the molecular basis of cell physiology and pathology of health-care problems such as metabolic defects, digestion, wound healing, sensory responses, and immunological defense against pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM057247-20
Application #
9390474
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Gindhart, Joseph G
Project Start
1998-08-01
Project End
2020-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
20
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Physiology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Greenberg, Michael J; Lin, Tianming; Shuman, Henry et al. (2015) Mechanochemical tuning of myosin-I by the N-terminal region. Proc Natl Acad Sci U S A 112:E3337-44
Shuman, Henry; Greenberg, Michael J; Zwolak, Adam et al. (2014) A vertebrate myosin-I structure reveals unique insights into myosin mechanochemical tuning. Proc Natl Acad Sci U S A 111:2116-21
Zwolak, Adam; Yang, Changsong; Feeser, Elizabeth A et al. (2013) CARMIL leading edge localization depends on a non-canonical PH domain and dimerization. Nat Commun 4:2523

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