Phylogenetic and functional classification of mitogen- and stress-activated protein kinases

• Published in: Journal of molecular evolution Vol. 46; no. 5; pp. 571 - 588
• Main Author: Kultz, D. (NHLBI, Bethesda, MD.)
• Format: Journal Article
• Language: English
• Published: Germany 01.05.1998
• Subjects: Amino Acid Sequence; AMINO ACID SEQUENCES; ANIMAL; ANIMALES; ANIMALS; BIOLOGICAL DIFFERENCES; Calcium-Calmodulin-Dependent Protein Kinases - chemistry; Calcium-Calmodulin-Dependent Protein Kinases - classification; Calcium-Calmodulin-Dependent Protein Kinases - physiology; CELLULE D'EUCARYOTE; CELULAS EUCARIOTICAS; CHAMPIGNON; CHEMICAL COMPOSITION; COMPOSICION QUIMICA; COMPOSITION CHIMIQUE; Conserved Sequence; DIFERENCIAS BIOLOGICAS; DIFFERENCE BIOLOGIQUE; EUCARYOTIC CELLS; EUKARYOTES; EXTRACELLULAR SIGNAL REGULATED KINASE; FILOGENIA; FOSFORILACION; FUNGI; HONGOS; Mice; MITOGEN ACTIVATED PROTEIN KINASE; Models, Molecular; MOLECULAR CONFORMATION; Molecular Sequence Data; MULTIPLE SEQUENCE ALIGNMENT; Mutagenesis; PHOSPHORYLATION; PHYLOGENIE; PHYLOGENY; PLANTAS; PLANTE; PLANTS; Protein Conformation; PROTEIN KINASE; PROTEINA QUINASA; PROTEINE KINASE; Rats; Sequence Alignment; SIGNATURE SEQUENCE; SPECIES DIFFERENCES
• ISSN: 0022-2844; 1432-1432
• DOI: 10.1007/PL00006338

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]XX[LIVM]XT[RK][WY]YRXPX[LIVM] [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 marine 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