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 #
5R37GM057247-21
Application #
9593509
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Gindhart, Joseph G
Project Start
1998-08-01
Project End
2020-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
21
Fiscal Year
2019
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
Mentes, Ahmet; Huehn, Andrew; Liu, Xueqi et al. (2018) High-resolution cryo-EM structures of actin-bound myosin states reveal the mechanism of myosin force sensing. Proc Natl Acad Sci U S A 115:1292-1297
Lebreton, G; Géminard, C; Lapraz, F et al. (2018) Molecular to organismal chirality is induced by the conserved myosin 1D. Science 362:949-952
Woody, Michael S; Capitanio, Marco; Ostap, E Michael et al. (2018) Electro-optic deflectors deliver advantages over acousto-optical deflectors in a high resolution, ultra-fast force-clamp optical trap. Opt Express 26:11181-11193
Iwamoto, Daniel V; Huehn, Andrew; Simon, Bertrand et al. (2018) Structural basis of the filamin A actin-binding domain interaction with F-actin. Nat Struct Mol Biol 25:918-927
Greenberg, Michael J; Shuman, Henry; Ostap, E Michael (2017) Measuring the Kinetic and Mechanical Properties of Non-processive Myosins Using Optical Tweezers. Methods Mol Biol 1486:483-509
Ghiretti, Amy E; Thies, Edda; Tokito, Mariko K et al. (2016) Activity-Dependent Regulation of Distinct Transport and Cytoskeletal Remodeling Functions of the Dendritic Kinesin KIF21B. Neuron 92:857-872
McIntosh, Betsy B; Ostap, E Michael (2016) Myosin-I molecular motors at a glance. J Cell Sci 129:2689-95
Pyrpassopoulos, Serapion; Arpa?, Göker; Feeser, Elizabeth A et al. (2016) Force Generation by Membrane-Associated Myosin-I. Sci Rep 6:25524
Greenberg, Michael J; Arpa?, Göker; Tüzel, Erkan et al. (2016) A Perspective on the Role of Myosins as Mechanosensors. Biophys J 110:2568-76
Arif, Ehtesham; Sharma, Pankaj; Solanki, Ashish et al. (2016) Structural Analysis of the Myo1c and Neph1 Complex Provides Insight into the Intracellular Movement of Neph1. Mol Cell Biol 36:1639-54

Showing the most recent 10 out of 20 publications