Our goal is to determine the molecular functions 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. Remarkably, the molecular functions of myosin-I are largely unknown, which is largely due to the lack of information about the basic biophysical properties of the proteins. Therefore, 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 mechanics and dynamics of the membrane- myosin-I interface, (2) mechanical and force generating properties of myosin-I, and (3) biochemical and mechanical properties of myosin-I binding 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 sensori-neural deficits, digestion, wound healing and immunological defense against pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM057247-16
Application #
8538995
Study Section
Macromolecular Structure and Function C Study Section (MSFC)
Program Officer
Gindhart, Joseph G
Project Start
1998-08-01
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
16
Fiscal Year
2013
Total Cost
$336,355
Indirect Cost
$126,133
Name
University of Pennsylvania
Department
Physiology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Pyrpassopoulos, Serapion; Arpağ, Göker; Feeser, Elizabeth A et al. (2016) Force Generation by Membrane-Associated Myosin-I. Sci Rep 6:25524
Greenberg, Michael J; Arpağ, Göker; Tüzel, Erkan et al. (2016) A Perspective on the Role of Myosins as Mechanosensors. Biophys J 110:2568-76
McIntosh, Betsy B; Ostap, E Michael (2016) Myosin-I molecular motors at a glance. J Cell Sci 129:2689-95
Kee, Anthony J; Yang, Lingyan; Lucas, Christine A et al. (2015) An actin filament population defined by the tropomyosin Tpm3.1 regulates glucose uptake. Traffic 16:691-711
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
Greenberg, Michael J; Shuman, Henry; Ostap, E Michael (2014) Inherent force-dependent properties of β-cardiac myosin contribute to the force-velocity relationship of cardiac muscle. Biophys J 107:L41-4
Ayloo, Swathi; Lazarus, Jacob E; Dodda, Aditya et al. (2014) Dynactin functions as both a dynamic tether and brake during dynein-driven motility. Nat Commun 5:4807
Pyrpassopoulos, Serapion; Shuman, Henry; Ostap, E Michael (2013) Method for measuring single-molecule adhesion forces and attachment lifetimes of protein-membrane interactions. Methods Mol Biol 1046:389-403
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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