Accurate multiple sequence alignment (MSA) is the major unsolved problem in protein bioinformatics. Alignments and similarity searches are essential first steps in experimental design for all studies involving proteins, and the accuracy of these methods is crucial for the success in biomedical research. In the course of this project, we plan to significantly improve the accuracy of alignments and the precision of sequence similarity detection between protein families. During the last few years, our group proposed 4 methods for MSA construction and 2 methods for remote homology inference. Presently, our latest program PROMALS3D is judged to be the most accurate aligner for weakly similar sequences. We also performed a comprehensive survey of kinase sequences and structures that revealed 25 homologous groups (superfamilies) in 10 structural folds. Building on these results, we propose to: 1) Improve sensitivity of sequence profile similarity search, mainly by using known relationships between database sequences. 2) Develop software for accurate MSA of sequences with low similarity. The emphasis is being made on employment of structural features and predictions to improve MSA quality. 3) Design an easy to use web server for exploration of protein families. The server could be queried with a single sequence to find, align and analyze its homologs, or with a set of sequences. The central component of the server is MSA using the software developed in this project. 4) Assemble a database of high quality MSAs for kinases and their relatives, and make testable structure-functional predictions for groups without experimental annotations. Since kinases attract considerable attention due to their medical relevance (e.g. cancer studies), this database should be a valuable asset to researchers.

Public Health Relevance

Accurate multiple sequence alignment is the major unsolved problem in protein bioinformatics. Alignments and sequence similarity searches are essential first steps in experimental design for all studies involving proteins, and the accuracy of these methods is crucial for the success of biomedical research. We will improve alignment accuracy and using the new method will analyze kinases, which are a medically important group of enzymes attracting high interest because of their relevance to many diseases, cancer in particular.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM094575-02
Application #
8098699
Study Section
Macromolecular Structure and Function D Study Section (MSFD)
Program Officer
Wehrle, Janna P
Project Start
2010-07-01
Project End
2014-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
2
Fiscal Year
2011
Total Cost
$305,984
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Li, Peng; Kinch, Lisa N; Ray, Ann et al. (2017) Acute Hepatopancreatic Necrosis Disease-Causing Vibrio parahaemolyticus Strains Maintain an Antibacterial Type VI Secretion System with Versatile Effector Repertoires. Appl Environ Microbiol 83:
Fédry, Juliette; Liu, Yanjie; Péhau-Arnaudet, Gérard et al. (2017) The Ancient Gamete Fusogen HAP2 Is a Eukaryotic Class II Fusion Protein. Cell 168:904-915.e10
Schaeffer, R Dustin; Liao, Yuxing; Cheng, Hua et al. (2017) ECOD: new developments in the evolutionary classification of domains. Nucleic Acids Res 45:D296-D302
Gao, Qiang; Binns, Derk D; Kinch, Lisa N et al. (2017) Pet10p is a yeast perilipin that stabilizes lipid droplets and promotes their assembly. J Cell Biol 216:3199-3217
Zhang, Jing; Cong, Qian; Fan, Xiao-Ling et al. (2017) Mitogenomes of Giant-Skipper Butterflies reveal an ancient split between deep and shallow root feeders. F1000Res 6:222
Pei, Jimin; Grishin, Nick V (2017) Expansion of divergent SEA domains in cell surface proteins and nucleoporin 54. Protein Sci 26:617-630
Cong, Qian; Shen, Jinhui; Li, Wenlin et al. (2017) The first complete genomes of Metalmarks and the classification of butterfly families. Genomics 109:485-493
Shen, Jinhui; Cong, Qian; Borek, Dominika et al. (2017) Complete Genome of Achalarus lyciades, The First Representative of the Eudaminae Subfamily of Skippers. Curr Genomics 18:366-374
Zhang, Jing; Kinch, Lisa N; Cong, Qian et al. (2017) Assessing predictions of fitness effects of missense mutations in SUMO-conjugating enzyme UBE2I. Hum Mutat 38:1051-1063
Cong, Qian; Shen, Jinhui; Borek, Dominika et al. (2016) Complete genomes of Hairstreak butterflies, their speciation, and nucleo-mitochondrial incongruence. Sci Rep 6:24863

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