The Faculty

Focus

Mechanisms of membrane protein biogenesis and quality control

Education

B.S., Biology & Chemistry, Bates College, 1990

Ph.D., Biochemistry & Biophysics, UCSF, 1998

Research Summary

Our research interfaces biology and chemistry to understand the molecular mechanisms that underlie fundamental biological processes. Current research topics include:

1. Membrane protein biogenesis. How are newly synthesized membrane proteins targeted to the correct intracellular membrane? Once there, how are they inserted into the bilayer? A major focus in the lab is the study of co- and post-translational targeting and insertion pathways. Our long-term goal is to decipher common structural and mechanistic themes in membrane protein biogenesis.

2. Membrane protein quality control. What happens to membrane proteins that fail to engage the targeting and insertion machinery? What happens if they are inserted into the wrong membrane? Or when a properly inserted membrane protein becomes damaged? To help protect against damage caused by such events, cells have evolved complex pathways that identify and destroy misfolded and/or mislocalized membrane proteins.

Selected Publications

Mateja A, Paduch M, Chang HY, Szydlowska A, Kossiakoff AA, Hegde RS, Keenan RJ. (2015). Structure of the Get3 targeting factor in complex with its membrane protein cargo. Science, 347:1152-1155. (doi: 10.1126/science.1261671).  

Hegde, R.S. and Keenan, R.J. (2011). Tail-anchored membrane protein insertion into the endoplasmic reticulum. Nat. Rev. Mol. Cell Biol., 12:787-798.; advance online publication (doi:10.1038/nrm3226).  

Mariappan, M.*, Mateja, A.*, Dobosz, M., Bove, E., Hegde, R.S. and Keenan, R.J. (2011) The mechanism of membrane-associated steps in tail-anchored protein insertion. Nature, 477:61-65; advance online publication, (doi:10.1038/nature10362).  

Sherrill, J., Mariappan, M., Dominik, P., Hegde, R.S. and Keenan, R.J., (2011) A conserved archaeal pathway for tail-anchored membrane protein insertion. Traffic, 12:1119-1123. 

Strack, R.L., Strongin, D.E., Mets, L., Glick, B.S. and Keenan, R.J. (2010) Chromophore formation in DsRed occurs by a branched pathway. J. Am. Chem. Soc., 132:8496-8505. 

Mateja, A., Szlachcic, A., Downing, M.E., Dobosz, M., Mariappan, M., Hegde, R.S. and Keenan, R.J. (2009) The structural basis of tail-anchored membrane protein recognition by Get3. Nature, 461:361-366; advance online publication, (doi:10.1038/nature08319).  

Strack, R.L., Strongin, D.E., Bhattacharyya, D., Tao, W., Berman, A., Broxmeyer, H.E., Keenan, R.J. and Glick, B.S. (2008) A noncytotoxic DsRed variant for whole-cell labeling. Nature Methods, 5:955-957. 

Keenan, R.J., Siehl, D.L., Gorton, R. and Castle, L.A. (2005). DNA shuffling as a tool for protein crystallization. Proc Natl Acad Sci USA, 102:8887-8892. 

Keenan, R.J., Freymann, D.M., Stroud, R.M. and Walter, P. (2001). The Signal Recognition Particle. Annu. Rev. Biochem., 70:755-775.  

Keenan, R.J., Freymann, D.M., Walter, P. and Stroud, R.M. (1998). Crystal Structure of the Signal Sequence Binding Subunit of the Signal Recognition Particle. Cell, 94:181-191.  

Freymann, D.M., Keenan, R.J., Stroud, R.M. and Walter, P. (1997). Structure of the conserved GTPase domain of the signal recognition particle. Nature, 385:361-364.