Phylogenetic and Functional Classification of Mitogen- and Stress-Activated Protein Kinases |
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Authors: | Dietmar Kültz |
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Institution: | (1) Laboratory of Kidney and Electrolyte Metabolism, NHLBI, National Institutes of Health, 10 Center Drive, MSC 1603, Building 10/Room 6N260, Bethesda, MD 20892-1603, USA, US |
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Abstract: | All currently sequenced stress-activated protein kinases (SAPKs), extracellular signal-regulated kinases (ERKs), and other
mitogen-activated protein kinases (MAPKs) were analyzed by sequence alignment, phylogenetic tree construction, and three-dimensional
structure modeling in order to classify members of the MAPK family. Based on this analysis the MAPK family was divided into
three subgroups (SAPKs, ERKs, and MAPK3) that consist of at least nine subfamilies. Members of a given subfamily were exclusively
from animals, plants, or yeast/fungi. A single signature sequence, LIVM]TS]XXLIVM]XTRK]WY]YRXPXLIVM] LIVM], was identified
that is characteristic for all MAPKs and sufficient to distinguish MAPKs from other members of the protein kinase superfamily.
This signature sequence contains the phosphorylation site and is located on loop 12 of the three-dimensional structure of
MAPKs. I also identified signature sequences that are characteristic for each of the nine subfamilies of MAPKs. By modeling
the three-dimensional structure of three proteins for each MAPK subfamily based on the resolved atomic structures of rat ERK2
and murine p38, it is demonstrated that amino acids conserved in all MAPKs are located primarily in the center of the protein
around the catalytic cleft. I conclude that these residues are important for maintaining proper folding into the gross structure
common to all MAPKs. On the other hand, amino acids conserved in a given subfamily are located mainly in the periphery of
MAPKs, indicating their possible importance for defining interactions with substrates, activators, and inhibitors. Within
these subfamily-specific regions, amino acids were identified that represent unique residues occurring in only a single subfamily
and their location was mapped in three-dimensional structure models. These unique residues are likely to be crucial for subfamily-specific
interactions of MAPKs with substrates, inhibitors, or activators and, therefore, represent excellent targets for site-directed
mutagenesis experiments.
Received: 13 August 1997 / Accepted: 21 November 1997 |
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Keywords: | : Extracellular signal-regulated kinase — Mitogen-activated protein kinase — Stress-activated protein kinase — Phosphorylation — Signature sequence — Signal transduction — Structure — Evolution |
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