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Figure legend: CHAIN analysis of Ran GTPases. Ran residues subject to strong selective constraints, as shown in the alignments, appear to play key roles in Ran’s C-terminal, basic patch, and nucleotide exchange mechanisms.
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Andrew Neuwald Associate Professor Ph.D., University of Iowa, 1987 Classification and modeling of protein domains; predicting protein structure, function and mechanisms email neuwald@cshl.edu, phone (516) 367-6802, fax (516) 367-8461
We aim to extract this information in the same way that a crystallographer extracts structural information from X-ray diffraction patterns. To do this, we have developed algorithmic and statistical procedures, including, for example, procedures for super-accurate multiple sequence alignment, for classification and estimation of selective constraints on specific residues, and for analysis of corresponding molecular interactions. The application of these and other, related procedures we term contrast hierarchical alignment and interaction network (CHAIN) analysis. The proteins most amenable to CHAIN analysis are those belonging to a large class consisting of well-conserved families and subfamilies, such as members of the AAA+ class of ATPases, signaling GTPases, and protein kinases. Further refined versions of these procedures are proving useful for smaller classes of proteins, such as DNA sliding clamps. In the future we plan to extend CHAIN analysis to many other core components of the cellular machinery. Selected Publications Neuwald, A.F. 1997. Barth syndrome may be due to an acyltransferase deficiency. Current Biology 7: R465-R466. This prediction led to clinical confirmation (see Schlame et al. 2003. J. American College Cardiology 42: 1994-1999) and to potential treatments for this disease.Liu, J. S., A.F. Neuwald and C. E. Lawrence. 1999. Markovian structures in biological sequence alignments. Journal of the American Statistical Association 94: 1-15. Awarded the year 2000 Mitchell prize. Neuwald, A.F. and T. Hirano. 2000. HEAT repeats associated with condensins, cohesins, and other complexes involved in chromosome-related functions. Genome Research 10: 1445-1452. This analysis led to the discovery of a new condensin component (see Ono, et al. 2003. Cell 115: 109-121). Neuwald, A.F., N. Kannan, A. Poleksic, N. Hata, and J.S. Liu. 2003. Ran’s C-terminal, basic patch, and nucleotide exchange mechanisms in light of a canonical structure for Rab, Rho, Ras, and Ran GTPases. Genome Research 13: 673–692. Neuwald, A.F. 2003. Evolutionary clues to DNA polymerase III b-clamp structural mechanisms. Nucleic Acids Research 31: 4503–4516. Kannan, N. and A.F. Neuwald. 2004. Evolutionary constraints associated with functional specificity of the CMGC protein kinases MAPK, CDK, GSK, SRPK, DYRK, and CK2. Protein Science, in press. |
We perform computational analysis of proteins that are well conserved
across the major divisions of life and which therefore constitute the
core of the cellular machinery. Although it is unclear why certain residues
in these proteins are conserved, the mere fact that they have persisted
over a billion years or more of evolution suggests that they form critical
interactions subject to specific geometric and/or chemical constraints.
Conserved sequence patterns reflect these functional constraints and
thus contain implicit information regarding underlying structural mechanisms.