THE MOTOR DOMAIN TRANSDUCER IS KEY FOR FUNCTIONAL TAILORING OF KINESINS
Document Type
Presentation
Start Date
22-10-2010 10:45 AM
End Date
22-10-2010 12:00 PM
Description
The amino acid sequence of a protein is intimately linked to its function. Case in point, a conserved catalytic core, termed the motor domain, is common to all motor proteins in the kinesin superfamily. The motor domain couples ATP hydrolysis to microtubule (MT) interactions, critical for a range of eukaryotic cellular functions that are targets for medical therapies. Recent studies in the field have begun to reveal an unanticipated breadth of motor-MT interactions, illustrating that motor domains are highly specialized, despite their high level of sequence similarity. The goal of this work is to locate a protein sector, responsible for tailoring the motor domain towards a specific cellular function. We hypothesize that regions of low sequence conservation in the motor domain contain information regarding how kinesins are customized. We performed a bioinformatics study, conducted in two parts: the first is phylogenetic analysis to organize the available kinesin sequence information and the second is computational assessment of nonconserved regions to locate potential protein sectors. Our dataset has 727 unique amino acid sequences from 78 individual taxa, resulting in one of the widest representations of kinesin sequences to date. Our phylogenetic tree is completely resolved with distinct branches representing 18 individual kinesin families, a difficult feat for such a large-scale effort. Computational assessment of nonconserved sequence regions, defined by examination of the entire superfamily dataset, identified a surprising result. Residues comprising the allosteric L5 insertion loop have kinesin family-specific consensus. Additionally, we observed family-specific sequence trends in residues comprising the central beta sheet of the motor domain. Together, the L5 loop and the central beta sheet comprise a protein sector that dictates separation and branch organization of our kinesin phylogeny. Prior studies have shown elements in this protein sector comprise the kinesin motor domain transducer, which coordinates the state of nucleotide hydrolysis with MT-interaction. Thus, sequence variation in the transducer may be responsible for tailoring the cellular function of the motor domain. As sites of the kinesin transducer are targets for small-molecule inhibition, this work suggests that biomedical therapies can be specifically customized to the kinesin appropriate for the disease.
Recommended Citation
Richard, Jessica; Kim, E.; and Kim, S., "THE MOTOR DOMAIN TRANSDUCER IS KEY FOR FUNCTIONAL TAILORING OF KINESINS" (2010). Dr. Joseph M. Moerschbaecher, III Graduate Research Day. 19.
https://digitalscholar.lsuhsc.edu/grad_rs/2010/poster1/19
THE MOTOR DOMAIN TRANSDUCER IS KEY FOR FUNCTIONAL TAILORING OF KINESINS
The amino acid sequence of a protein is intimately linked to its function. Case in point, a conserved catalytic core, termed the motor domain, is common to all motor proteins in the kinesin superfamily. The motor domain couples ATP hydrolysis to microtubule (MT) interactions, critical for a range of eukaryotic cellular functions that are targets for medical therapies. Recent studies in the field have begun to reveal an unanticipated breadth of motor-MT interactions, illustrating that motor domains are highly specialized, despite their high level of sequence similarity. The goal of this work is to locate a protein sector, responsible for tailoring the motor domain towards a specific cellular function. We hypothesize that regions of low sequence conservation in the motor domain contain information regarding how kinesins are customized. We performed a bioinformatics study, conducted in two parts: the first is phylogenetic analysis to organize the available kinesin sequence information and the second is computational assessment of nonconserved regions to locate potential protein sectors. Our dataset has 727 unique amino acid sequences from 78 individual taxa, resulting in one of the widest representations of kinesin sequences to date. Our phylogenetic tree is completely resolved with distinct branches representing 18 individual kinesin families, a difficult feat for such a large-scale effort. Computational assessment of nonconserved sequence regions, defined by examination of the entire superfamily dataset, identified a surprising result. Residues comprising the allosteric L5 insertion loop have kinesin family-specific consensus. Additionally, we observed family-specific sequence trends in residues comprising the central beta sheet of the motor domain. Together, the L5 loop and the central beta sheet comprise a protein sector that dictates separation and branch organization of our kinesin phylogeny. Prior studies have shown elements in this protein sector comprise the kinesin motor domain transducer, which coordinates the state of nucleotide hydrolysis with MT-interaction. Thus, sequence variation in the transducer may be responsible for tailoring the cellular function of the motor domain. As sites of the kinesin transducer are targets for small-molecule inhibition, this work suggests that biomedical therapies can be specifically customized to the kinesin appropriate for the disease.