Center for Protein Chemistry
The IMM is the hub of a new alliance connecting research efforts across the university in systems biology, clinical and translational sciences, protein chemistry, genomics, and proteomics. This new multidisciplinary science will link the efforts of various centers, bringing together people to promote intellectual exchange and the transfer of expertise in these key fields and beyond.
Phone 713.500.2458; fax 713.500.2447
Chuantao Jiang, Research Assistant Professor Center for Protein Chemistry, MD, PhD
The Center for Protein Chemistry examines the structural analysis of proteins while addressing a range of diseases, inlcluding neurodegenerative diseases. Current and past research activities of the Center for Protein Chemistry focus on four major areas of interest:
(1) Development of sensitive methodologies for structural characterization of peptides and proteins. The Center has contributed in the past to the development of a number of methodologies that permit high sensitivity structural characterization of proteins. A paper describing micro-sequencing of proteins (Chang et al. FEBS Lett 1978; 93:205-214) was a Citation Classic (Current Contents 1991; June 17, p.10). A method for high sensitivity amino acid analysis (Dabsyl Chloride method) has been cited in three major biochemistry textbooks for undergraduate studies (Biochemistry 1995 by Stryer, p.54; Principles of Biochemistry 1993 by Lehninger, Helson and Cox, pp. 124-127).
(2) Characterization of structure and function of proteins. The Center was the first to propose the specific interaction between the hirudin C-terminal domain and the fibrinogen recognition site of thrombin (Chang, FEBS Lett 1983; 164:307-313). This proposed mechanism has led to the design, synthesis and commercialization of a new class of anticoagulant (Hirulog) for the treatment of deep vein thrombosis by various pharmaceutical companies, including Biogen and Merrel-Dow and Hoechst.
(3) Elucidation of the pathway(s) of protein folding and unfolding. The Center also leads investigations into the mechanisms that determine the folding and unfolding (denaturation) of disulfide proteins. The fundamental mechanism of protein folding and unfolding is the underlying cause behind a number of neurodegenerative diseases including Prion disease, Parkinson's disease and Alzheimer's disease. We have elucidated the folding and unfolding pathways of 16 different disulfide proteins, including hirudin, EGF, IGF, leech carboxypeptidase inhibitor, tick anticoagulant protein and bovine alpha-interferon etc. These studies demonstrate the vast diversity of the protein folding mechanism (Trends in Biochem. Sci. 2006; 31:292-301).
During the course of these studies, the laboratory was the first to propose and describe that scrambled structures of disulfide-containing proteins (also known as X-isomers), contrary to the conventional wisdom that they represent products of abortive folding, are indeed essential intermediates along the pathway of productive protein folding (JBC 1993; 270:20988-20996; JBC 1995; 270:25661-25666). This finding has potential impact on our current view of protein folding, stability and turnover. The laboratory also developed the novel “disulfide scrambling” technique for studying the mechanism of protein unfolding (JBC 2001; 276:9705-9712) and refolding (JBC 2002; 277:120-126).
(4) Production of stabilized non-native protein isomers and characterization of their biological and immunological properties. Our current research activity focuses on the structural and functional analysis of stabilized isomers (X-isomers) of denatured proteins. Denatured proteins comprise highly heterogeneous conformational isomers. Denatured proteins are also typically devoid of their intended biological activities. Due to the complexity of structure and the lack of biological function, structural and functional analysis of denatured proteins has been generally regarded as a daunting and futile effort. However, the importance of characterizing denatured protein is mounting in recent years. Conformational change of proteins has proven to be an underlying cause of many neurodegenerative diseases. Any attempt to elucidate the mechanism of these diseases would have to entail meticulous characterization of diverse isomers of disease-associated proteins. In addition, conformational isomers of denatured proteins are conceivably one of the most opulent resources of bio-molecules that have remained untapped for their potential use in the disease diagnosis and treatment.
Despite the emerging significance, structure and function analysis of denatured proteins remains inherently difficult because the unfeasibility of isolating denatured conformational isomers. To overcome this problem, our laboratory has developed a method for preparation of stabilized conformational isomers of denatured proteins (X-isomers) that are amenable to isolation, characterization and further applications (JBC 1999; 274:123-128)(JBC 2001; 276:9705-9712). Our initial studies with X-isomers of disease associated proteins demonstrate that they are able to break the immune tolerance. X-isomers exhibit enhanced aggregation and increase immunogenicity as compared to the native protein. They are potential immunogens for production of antibody and development of therapeutic vaccines. Several X-isomers of disease-associated proteins, including prion protein, beta-amyloid protein and alpha-synuclein are currently in production and testing in our laboratory.