Personal Summary

Levi McClelland is a Research Assistant Professor and Manager of the Integrated Structural Biology Core at the University of Montana (UM). He received his PhD in Biochemistry and Biophysics (2015) in Bruce Bowler’s Lab (UM) studying protein stability and conformational changes associated with pH sensitivity. To better understand structural effects of conformational change, he collaborated with Stephen Sprang’s Lab (UM) to solve novel cytochrome c crystal structures of interest. Postdoctoral work in the Sprang Lab yielded further experience in protein macromolecular crystallography and small-angle X-ray scattering, solving the structure of G-alpha protein subunit i complexed to its chaperone/nucleotide exchange factor Ric-8A. Upon completion of his postdoctoral studies (2020), Dr. McClelland joined the Center for Biomolecular Structure and Dynamics as the manager of the Integrated Structural Biology Core, providing protein expression and macromolecular structural services for the UM community. Current research areas focus on biochemical, biophysical, and structural biology chemistry.

Education

B.S. in Biochemistry from Slippery Rock University, Slippery Rock – Pennsylvania, 2009.

Ph.D. in Biochemistry and Biophysics with Bruce Bowler at the University of Montana, Missoula – Montana, 2015.

Postdoctoral studies with Stephen Sprang at the University of Montana, Missoula – Montana, 2015-2020.

Research Interests

Gα subunits are integral components of G protein coupled receptor signaling pathways, which are pharmacologically targeted due to their diverse involvement in cellular regulation. Ric-8 is a cytosolic guanine nucleotide exchange factor (GEF) and Gα chaperone required for Gα biosynthesis and has been proposed as an untapped pharmacological target in G-protein signaling. Although we have solved the crystal and Cryo-EM structures of Ric-8A in complex with Gαi, the intricacies modulating Ric-8A activity towards Gα are ongoing.

Neuronal calcium sensor 1 (NCS-1) is a highly conserved and widely expressed calcium sensor implicated in neuronal growth and pathological roles in human neurological disease and neurodegeneration. NCS-1 binds Ric-8A under low Ca²⁺ conditions and is hypothesized to release Ric-8A upon sensing a Ca²⁺ surge. Formation of the NCS-1:Ric-8A complex prevents Ric-8A interaction with Gα subunits, although very little data is available on the role of NCS-1 in regulating Ric-8A. Current work includes understanding the role of NCS-1 regulation of Ric-8A guanine nucleotide exchange factor (GEF) activity towards Gα subunits. Using tryptophan fluorescence assays, we directly measure the GEF activity of Ric-8A in the presence and absence of NCS-1 and Ca²⁺. Structural characterization of NCS-1:Ric-8A is in progress. 

Publications

Muñoz-Reyes, McClelland, Arroyo-Urea, Sánchez-Yepes, Sabin, Pérez-Suárez, Menéndez, Mansilla, García-Nafría, Sprang, Sánchez-Barrena.  The neuronal calcium sensor NCS-1 regulates the phosphorylation state and activity of the G chaperone and GEF Ric-8A.  BioRxiv  doi: https://doi.org/10.1101/2022.12.09.519724. 

McClelland LJ, Zhang K, Mou TC, Johnston J, Yates-Hansen C, Li S, Thomas CJ, Doukov TI, Triest S, Wohlkonig A, Tall GG, Steyaert J, Chiu W, Sprang SR. Structure of the G protein chaperone and guanine nucleotide exchange factor Ric-8A bound to Gαi1. Nat Commun. 2020 Feb 26;11(1):1077. PubMed PMID: 32103024; PubMed Central PMCID: PMC7044438.

McClelland LJ, Steele HB, Whitby FG, Mou TC, Holley D, Ross JB, Sprang SR, Bowler BE. Cytochrome c Can Form a Well-Defined Binding Pocket for Hydrocarbons. J Am Chem Soc. 2016 Dec 28;138(51):16770-16778. PubMed PMID: 27990813; PubMed Central PMCID: PMC5564421. 

McClelland LJ, Bowler BE. Lower Protein Stability Does Not Necessarily Increase Local Dynamics. Biochemistry. 2016 May 17;55(19):2681-93. PubMed PMID: 27104373. 

Goldes ME, Jeakins-Cooley ME, McClelland LJ, Mou TC, Bowler BE. Disruption of a hydrogen bond network in human versus spider monkey cytochrome c affects heme crevice stability. J Inorg Biochem. 2016 May;158:62-69. PubMed PMID: 26775610; PubMed Central PMCID: PMC4887337. 

McClelland LJ, Seagraves SM, Khan MK, Cherney MM, Bandi S, Culbertson JE, Bowler BE. The response of Ω-loop D dynamics to truncation of trimethyllysine 72 of yeast iso-1-cytochrome c depends on the nature of loop deformation. J Biol Inorg Chem. 2015 Jul;20(5):805-19. PubMed PMID: 25948392; PubMed Central PMCID: PMC4485566. 

McClelland LJ, Mou TC, Jeakins-Cooley ME, Sprang SR, Bowler BE. Structure of a mitochondrial cytochrome c conformer competent for peroxidase activity. Proc Natl Acad Sci U S A. 2014 May 6;111(18):6648-53. PubMed PMID: 24760830; PubMed Central PMCID: PMC4020089.