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Biomedical subjects

Michael J Corboy

Publications and source records attributed to Michael J Corboy.

4 recordsLinked to original sources
PubMed2005

Aggresome formation.

Bulk protein degradation in the cell is catalyzed by the ubiquitin-proteasome system (UPS). At the heart of the UPS is the proteasome, a large multisubunit tightly-regulated protease. The UPS performs key functions in protein quality control by monitoring and eliminating potentially toxic misfolded or damaged proteins. When the capacity of this protease system is exceeded, misfolded protein substrates aggregate and are assembled through an active and regulated process to form an aggresome. Aggresomes are dynamic structures, formed as a general response to an overload of improperly folded proteins. Assembly of aggresomes occurs at the centrosome, a perinuclear structure that also serves as a site for the recruitment and concentration of components of the UPS, including the proteasome, its regulators, and other proteins typically involved in protein quality control. Thus, in addition to other cellular activities, the centrosome may play a central role in protein quality control, sitting at the crossroads of protein folding, degradation, and aggregation.

Cell Line↗
PubMed2002

Endoproteolytic activity of the proteasome.

The proteasome plays a central role in the degradation of regulatory and misfolded proteins. Current models suggest that substrates access the internal catalytic sites by processively threading their termini through the gated substrate channel. Here, we found that latent (closed) and activated (open) proteasomes degraded two natively disordered substrates at internal peptide bonds even when they lacked accessible termini, suggesting that these substrates themselves promoted gating of the proteasome. This endoproteolysis provides a molecular mechanism for regulated release of transcription factors from inactive precursors as well as a means of accessing internal folding defects of misfolded multidomain proteins.

Amino Acid Sequence↗
PubMed2002

A protein sequence that can encode native structure by disfavoring alternate conformations.

The linear sequence of amino acids contains all the necessary information for a protein to fold into its unique three-dimensional structure. Native protein sequences are known to accomplish this by promoting the formation of stable, kinetically accessible structures. Here we describe a Pro residue in the center of the third transmembrane helix of the cystic fibrosis transmembrane conductance regulator that promotes folding by a distinct mechanism: disfavoring the formation of a misfolded structure. The generality of this mechanism is supported by genome-wide transmembrane sequence analyses. Furthermore, the results provide an explanation for the increased frequency of Pro residues in transmembrane alpha-helices. Incorporation by nature of such 'negative folding determinants', aimed at preventing the formation of off-pathway structures, represents an additional mechanism by which folding information is encoded within the evolved sequences of proteins.

Amino Acid Sequence↗