# Molecular Analysis of Flagellar Dynein Function

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2020 · $407,224

## Abstract

Motile cilia and flagella play key roles in development, fertility, and organismal homeostasis; in humans, defects
result in a broad array of phenotypes such as male/female infertility, hydrocephalus, severe bronchial problems
and heart malformations. Cilia contain more than 700 distinct protein components and indeed, more than 5% of
all human genes are involved in the assembly or function of these motile/sensory organelles. Ciliary motility is
powered by the highly complex inner and outer dynein arm motors whose activity results in inter-doublet
microtubule (MT) sliding and ciliary beating. However, the molecular mechanisms by which dyneins and other
ciliary subsystems are pre-assembled in cytoplasm, docked at specific axonemal locations, and how their activity
is controlled by the mechanical state or curvature of the axoneme to generate and propagate specific waveforms
remain very unclear. In this proposal we will address key aspects of these fundamental problems in ciliary
biology using two model organisms with very complementary attributes: Chlamydomonas will be used for
genetic/biochemical and structural approaches, whereas RNAi methods in planaria will be employed to assess
the function of novel factors in the context of a ciliated epithelium where thousands of motile cilia are
synchronized through hydrodynamic coupling. We recently found that a WD-repeat protein (WDR92), which
interacts with a prefoldin-like co-chaperone complex, is necessary to build fully functional motile cilia; lack of
WDR92 results in axoneme assembly defects including missing dynein arms, incomplete outer doublet MTs and
failure of the central pair complex to form. In Aim 1 we will use biochemical methods in Chlamydomonas to
identify WDR92-interacting components in cytoplasm and then test their role in ciliary formation and function in
planaria, as this will provide new paradigms for understanding how cytoplasmic factors influence the coordinate
assembly of axonemal substructures. Once trafficked into the ciliary compartment, assembling outer arm
dyneins at precise locations is a multi-factorial process that requires both specific docking proteins within the
axonemal superstructure and soluble components in the ciliary matrix. In Aim 2, we will use
biochemical/structural methods to define the mechanistic roles of two essential components in the precisely
patterned assembly of the outer dynein arm that is absolutely critical for building a fully functional organelle.
Axonemal dyneins must sense and respond to the curvature that they experience in order for regions of active
sliding to oscillate across the structure and to propagate a wave of motor activity along the organelle generating
a ciliary beat. We have predicted that the leucine-rich repeat protein LC1 which binds MTs and also associates
with the MT-binding domain of one dynein heavy chain is key to this mechano-switching. In Aim 3, we will use
a newly available LC1 null mutant to rigorously test these mechani...

## Key facts

- **NIH application ID:** 9914102
- **Project number:** 5R01GM051293-25
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Stephen M King
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $407,224
- **Award type:** 5
- **Project period:** 1995-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9914102

## Citation

> US National Institutes of Health, RePORTER application 9914102, Molecular Analysis of Flagellar Dynein Function (5R01GM051293-25). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9914102. Licensed CC0.

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