# Mechanistic Analysis of Microtubule Based Motors

> **NIH NIH R37** · RENSSELAER POLYTECHNIC INSTITUTE · 2021 · $461,903

## Abstract

The overarching goal is to gain critical insights into the fundamentals of kinesin motor structure and
function and to extrapolate this understanding to the inner workings of the cell. Kinesin superfamily members
share a common catalytic domain yet participate in a wide range of cellular functions including intracellular
transport, mitosis and meiosis, regulation of microtubule dynamics for remodeling of the cytoskeleton, and
generation of cell polarity. It is now recognized that sequence differences modify the mechanochemistry,
microtubule interactions, and the response to force, each of which is critical for the specific physiological
function. The goal of this proposal is to establish the mechanistic and structural features shared by kinesin-
14 Kar3Cik1, Kar3Vik1, and Ned and at the same time to reveal unique features that result in functional
specificity. Members of the kinesin-14 subfamily are the only kinesins known to promote microtubule minus-
end-directed force generation and to use an ATP-promoted powerstroke mechanism. In contrast, members
of kinesin-1, 2, 5, and 7 subfamilies generate microtubule plus-end-directed force, and these molecular
motors are processive. Conventional kinesin-1, kinesin-5 Eg5, and kinesin-7 CENP-E generate dimeric
motors from the same gene product, yet the functional catalytic dimer for kinesin-2 KIF3AB and KIF3AC
arises from two different gene products. Therefore, what is the selective advantage of heterodimeric catalytic
enzymes for in vivo function, how is head-head communication established to modulate interactions with the
microtubule lattice and/or microtubule end, and what mechanisms regulate the interplay of processivity and
response to force? The research proposed evaluates heterodimeric Kar3Cik1 and Kar3Vik1 in comparison to
homodimeric Ned, and heterodimeric Kinesin-2 KIFAB and KIFAC in comparison to other processive
homodimeric kinesins. Experimental approaches include presteady-state kinetics methodologies, single
molecule and ensemble fluorescence microscopy, optical trapping to determine the force-dependent motility
properties, X-ray crystallography, cryo-electron microscopy and tomography, and computational modeling.
This comprehensive analysis will provide new insights to understand the mechanochemistry that underlies
structure-function relationships required for cellular organization and physiological function.
RELEVANCE (See instructions):
The overall goal is to understand the mechanochemistry of kinesin motors that underlies their ability to
promote intracellular transport, generation of cell polarity, and remodeling of the microtubule cytoskeleton for
cell division, cell differentiation, and morphogenesis during human development. Defects in kinesins have
been linked to diverse pathologies including cancer, ciliopathies, neuropathies, and birth defects.

## Key facts

- **NIH application ID:** 10135979
- **Project number:** 5R37GM054141-27
- **Recipient organization:** RENSSELAER POLYTECHNIC INSTITUTE
- **Principal Investigator:** SUSAN P. GILBERT
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $461,903
- **Award type:** 5
- **Project period:** 1996-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10135979

## Citation

> US National Institutes of Health, RePORTER application 10135979, Mechanistic Analysis of Microtubule Based Motors (5R37GM054141-27). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10135979. Licensed CC0.

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