Malaiyalam Mariappan

Assistant Professor of Cell Biology

Research Interests

Membrane protein homeostasis, targeting and insertion, assembly; Misfolded membrane protein degradation; Biochemical reconstitution

Research Summary

Our lab aims to understand the mechanisms by which cells maintain membrane protein homeostasis. Because membrane proteins are hydrophobic in nature, they are at constant risk for mistargeting, misfolding, and aggregation in the cell. To solve these problems, cells have evolved with sophisticated strategies that facilitate membrane protein targeting, insertion, assembly and degradation. We are interested in identifying and understanding machinery of proteins necessary for such processes. This study has implications for understanding human diseases including various neurodenerative disorders and cystic fibrosis, which are caused by defects in membrane protein homeostasis. We are focusing on three main research areas:

  1. Membrane protein targeting and insertion;
  2. Assembly of membrane protein complexes at the membrane;
  3. Misfolded membrane protein degradation.

Extensive Research Description

  • Membrane protein targeting and insertion. Prior to membrane insertion, hydrophobic transmembrane domains of membrane proteins are prone to mistargeting, misfolding, and aggregation in the cell. This phenomenon raises important questions. What molecules prevent membrane proteins from these off-pathway intermediates? How are proteins inserted into a correct membrane in cells? Recently, we have discovered a cascade of chaperones involved in post-translational targeting of membrane proteins to the endoplasmic reticulum (ER). In future studies, we want to understand how these chaperones work together to move membrane proteins through the aqueous cytosol to achieve correct targeting. We are using a combination of biochemical reconstitution and biophysical approaches to address this problem.
  • Assembly of membrane protein complexes at the membrane. Many important biological processes are performed by membrane protein complexes at the membrane. Examples include cell-cell communication, antigen presentation, and viral assembly. However, it is largely unknown how multi-protein complexes are assembled at the membrane, and how unassembled proteins are eliminated from the membrane. We are developing in vitro cell-free and in vivo FRET based assays to identify and understand membrane factors that facilitate assembly of membrane protein complexes.
  • Misfolded membrane protein degradation. Cell function and viability critically depend on recognition and elimination of misfolded proteins to avoid accumulation of toxic aggregates. Nowhere is the misfolding of proteins more frequent than in the ER where proteins with complex topology and multiple transmembrane domains are synthesized. These misfolded membrane proteins are destroyed via the ER associated degradation (ERAD) pathway. ERAD is associated with many human diseases, however, little is known about the molecules and mechanisms involved in the degradation of membrane proteins. For example, when and how are misfolded membrane proteins detected? How are transmembrane domains of membrane proteins extracted from membranes? How are hydrophobic transmembrane domains shielded from aggregation during targeting to the proteasome for degradation? To answer these questions and understand this process in detail, we are developing an in vitro cell-free system with the mutant form of CFTR membrane protein that causes cystic fibrosis. The high manipulability of this in vitro system should allow us to test each component and identify novel factors involved in this process. Our ultimate goal is to reconstitute the misfolded membrane protein degradation from purified components and dissect its mechanistic details.

Selected Publications

  • *Mariappan, M., *Mateja, A., Dobosz, M., Bove, E., Hegde, R. S., and Keenan, R. J. (2011) The mechanisms of membrane associated steps in tail-anchored protein insertion. Nature 477, 61-66.
  • Hessa, T., Sharma, A., Mariappan, M., Eshleman, H. D., Gutierrez, E., and Hegde, R. S. (2011) Protein targeting and degradation pathways are coupled for elimination of mislocalized proteins. Nature 475, 393-397.
  • Mariappan, M., Li, X., Stefanovic, S., Sharma, A., Mateja, A., Keenan, R. J., and Hegde, R. S. (2010) A ribosome-associating factor chaperones tail-anchored membrane proteins. Nature 466, 1120-1124.
  • 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.
  • Mariappan, M., Gande, S. L., Radhakrishnan, K., Schmidt, B., Dierks, T., and von Figura, K. (2008) The non-catalytic N-terminal extension of formylglycine-generating enzyme is required for its biological activity and retention in the endoplasmic reticulum. J. Biol. Chem. 283, 11556-11564.
  • Dierks, T., Dickmanns, A., Preusser-Kunze, A., Schmidt, B., Mariappan, M., von Figura, K., Ficner, R., and Rudolph, M. G. (2005) Molecular basis for multiple sulfatase deficiency and mechanism for formylglycine generation of the human formylglycine-generating enzyme. Cell 121, 541-552.

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