Department of Chemistry and Biochemistry


Matthew Wohlever, PhD
Assistant Professor
Department of Chemistry and Biochemistry
Office: WO 3210B
Phone: 419.530.8401

Professional Background:
B.S. - Ohio State University
Ph.D. - Massachusetts Institute of Technology

Group Web Site

Research Synopsis: 

Organelles with distinct membrane proteomes are a hallmark of eukaryotic cells. Failures in membrane protein homeostasis (proteostasis) disrupt organelle function leading to many diseases, including cancer and neurodegeneration. Despite its importance, our understanding of membrane proteostasis is sparse. My lab will focus on two key questions in membrane protein quality control: (1) what happens to membrane proteins that insert into the wrong membrane; and (2) what happens to membrane proteins that fail to insert at all? My lab will take a “bottom-up” approach, with the long-term goal of using these mechanistic studies as a springboard for pathway discovery broadly related to the biogenesis and quality control of membrane proteins and the physiological consequences of misregulation of these essential processes.

Mistargeting of proteins to the wrong membrane leads to compromised organelle function unless the mislocalized proteins are promptly removed. However, our understanding of this essential process is poor. My lab will address this by focusing on Msp1, a highly conserved AAA+ ATPase anchored in the outer mitochondrial membrane that is proposed to selectively remove mislocalized tail-anchored membrane proteins (Figure 1). Loss of Msp1 leads to severe mitochondrial defects, seizures, and early death. During my postdoc, I developed a reconstituted system with fully purified components and used structural analysis to show that Msp1 is necessary and sufficient to extract tail-anchored membrane proteins from the bilayer. My lab will use this reconstituted system to study how Msp1 can selectively recognize and extract these mislocalized proteins.


When insertion fails, membrane proteins must be quickly triaged to prevent the formation of potentially toxic aggregates, but little is known about how this triage decision is made. In collaboration with Manu Hegde’s Lab, we recently showed that Ubiquilins are molecular chaperones that triage mitochondrial membrane proteins. Ubiquilins directly bind to the TMD of mitochondrial membrane proteins and recruit other components of the quality control system including Hsp70, E3 ligases, and the proteasome to facilitate membrane insertion or degradation (Figure 2). Humans have three widely expressed Ubiquilins (UBQLN1, 2, & 4), all of which have mutations linked to neurodegenerative diseases, including ALS, Huntington’s and Alzheimer’s disease. However, the role of Ubiquilins in quality control is only understood in broad terms and the defects of disease associated mutants are unknown. My lab will examine the molecular mechanism of Ubiquilin function in quality control and neurodegenerative disease. 


Last Updated: 5/27/20