Understanding how genetic information is translated into protein is one of the classic problems in molecular biology. However it is increasingly clear that synthesis of a primary amino acid sequence represents only the very first step in generation of a functional protein product. A newly synthesized polypeptide must be folded, localized to the correct cellular compartment, and ultimately complexed with its interacting partners before it can carry out its biological role. Furthermore, each of these steps is tightly coupled to a quality control pathway that must identify and ultimately degrade those messenger RNAs and proteins that fail at any stage of their maturation. Defects in these downstream biosynthetic and surveillance pathways underlie a variety of human diseases. Yet far less is known about how the factors responsible for these processes cooperate with the protein synthesis machinery to ensure proteome fidelity and prevent disease.
Our lab aims to understand two primary questions: i) the molecular mechanism of protein biosynthesis and assembly and ii) how the cell recognizes and degrades messenger RNAs and proteins that fail during maturation. We do this using a combination of structural and functional strategies, including in vitro reconstitution, biochemical and cell based assays, and cryo-electron microscopy (cryo-EM).
R. Voorhees and R. Hegde. Structure of the Sec61 translocation channel opened by a signal sequence. Science. 2016
R. Voorhees and R. Hegde. Structures of the scanning and engaged states of the mammalian SRP-ribosome complex. eLife. 2015.
R. Voorhees#, I. Fernandez, S. Scheres, and R. Hegde#. Structure of the mammalian ribosome-Sec61 complex to 3.4 Å resolution. Cell. 2014. #Co-corresponding authors.
R.Voorhees, T. Schmeing, A. Kelley, and V. Ramakrishnan. The mechanism for activation of GTP hydrolysis on the ribosome. Science. 2010.
T. Schmeing*, R. Voorhees*, A. Kelley, Y. Gao, F. Murphy, J. Weir, and V. Ramakrishnan. The crystal structure of the ribosome bound to EF-Tu and aminoacyl-tRNA. Science. 2009. *These authors contributed equally to this work.