Combining multiple structure and sequence alignments to improve sequence detection and alignment: Application to the SH2 domains of Janus kinases Export

@article{citeulike:735025, abstract = {10.1073/pnas.011577898 In this paper, an approach is described that combines multiple structure alignments and multiple sequence alignments to generate sequence profiles for protein families. First, multiple sequence alignments are generated from sequences that are closely related to each sequence of known three-dimensional structure. These alignments then are merged through a multiple structure alignment of family members of known structure. The merged alignment is used to generate a Hidden Markov Model for the family in question. The Hidden Markov Model can be used to search for new family members or to improve alignments for distantly related family members that already have been identified. Application of a profile generated for SH2 domains indicates that the Janus family of nonreceptor protein tyrosine kinases contains SH2 domains. This conclusion is strongly supported by the results of secondary structure-prediction programs, threading calculations, and the analysis of comparative models generated for these domains. One of the Janus kinases, human TYK2, has an SH2 domain that contains a histidine instead of the conserved arginine at the key phosphotyrosine-binding position, \^{I}²B5. Calculations of the pK values of the \^{I}²B5 arginines in a number of SH2 domains and of the \^{I}²B5 histidine in a homology model of TYK2 suggest that this histidine is likely to be neutral around pH 7, thus indicating that it may have lost the ability to bind phosphotyrosine. If this indeed is the case, TYK2 may contain a domain with an SH2 fold that has a modified binding specificity.}, author = {Al-Lazikani, Bissan and Sheinerman, Felix B. and Honig, Barry}, booktitle = {Proceedings of the National Academy of Sciences of the United States of America}, citeulike-article-id = {735025}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.011577898}, citeulike-linkout-1 = {http://www.pnas.org/content/98/26/14796.abstract}, citeulike-linkout-2 = {http://www.pnas.org/content/98/26/14796.full.pdf}, citeulike-linkout-3 = {http://www.pnas.org/cgi/content/abstract/98/26/14796}, citeulike-linkout-4 = {http://view.ncbi.nlm.nih.gov/pubmed/11752426}, citeulike-linkout-5 = {http://www.hubmed.org/display.cgi?uids=11752426}, day = {18}, doi = {10.1073/pnas.011577898}, journal = {PNAS}, month = {December}, number = {26}, pages = {14796--14801}, posted-at = {2009-01-21 10:58:50}, priority = {2}, title = {Combining multiple structure and sequence alignments to improve sequence detection and alignment: Application to the SH2 domains of Janus kinases}, url = {http://dx.doi.org/10.1073/pnas.011577898}, volume = {98}, year = {2001} }

TY - JOUR ID - citeulike:735025 L3 - citeulike-article-id:735025 N2 - 10.1073/pnas.011577898 In this paper, an approach is described that combines multiple structure alignments and multiple sequence alignments to generate sequence profiles for protein families. First, multiple sequence alignments are generated from sequences that are closely related to each sequence of known three-dimensional structure. These alignments then are merged through a multiple structure alignment of family members of known structure. The merged alignment is used to generate a Hidden Markov Model for the family in question. The Hidden Markov Model can be used to search for new family members or to improve alignments for distantly related family members that already have been identified. Application of a profile generated for SH2 domains indicates that the Janus family of nonreceptor protein tyrosine kinases contains SH2 domains. This conclusion is strongly supported by the results of secondary structure-prediction programs, threading calculations, and the analysis of comparative models generated for these domains. One of the Janus kinases, human TYK2, has an SH2 domain that contains a histidine instead of the conserved arginine at the key phosphotyrosine-binding position, βB5. Calculations of the pK values of the βB5 arginines in a number of SH2 domains and of the βB5 histidine in a homology model of TYK2 suggest that this histidine is likely to be neutral around pH 7, thus indicating that it may have lost the ability to bind phosphotyrosine. If this indeed is the case, TYK2 may contain a domain with an SH2 fold that has a modified binding specificity. IS - 26 JF - PNAS EP - 14801 TI - Combining multiple structure and sequence alignments to improve sequence detection and alignment: Application to the SH2 domains of Janus kinases VL - 98 T2 - Proceedings of the National Academy of Sciences of the United States of America SP - 14796 AU - Al-Lazikani, Bissan AU - Sheinerman, Felix AU - Honig, Barry PY - 2001/12/18/ UR - http://dx.doi.org/10.1073/pnas.011577898 ER -