Abstract
Purpose :
Photoreceptors, such as rods and cones, rely on cilia to transduce photons into neural impulses, resulting in vision. In certain inherited conditions, the synthesis or function of cilia is negatively affected (ciliopathies), resulting in vision loss. Kinesin-2 is a heterotrimeric protein consisting of two heterodimeric heavy chains (KIF3A & KIF3B) and a non-motor protein (KAP. Here, we study how kinesin-2 powers the anterograde IFT in primary cilia and determine the pathophysiology of retinitis pigmentosa (RP) caused by a dominant KIF3B mutation.
Methods :
A combination of structural, cell biological, and in vitro single-molecule approaches were utilized to characterize mutated KIF3B enzymatic activity and overall function.
Results :
We show that kinesin-2 adapted a unique stepping mechanism optimized for IFT transport. Our initial analysis indicates that the RP disease mutation disrupts kinesin-2 motor coordination, leading to a dominant transport defect in which normal motors cannot compensate during ciliary trafficking.
Conclusions :
Besides a new mechanistic understanding of retinal diseases, our research contributes a novel reconstituted system that permits direct interrogation of the retinal cytoskeleton in vitro.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.