Mitogen-activated protein (MAP) kinase ERK2
Rattus norvegicus (rat)
MAP kinases are protein phosphotransferases and are activated by several factors related to cancer or cell growth. These enzymes function as monomers and consist of only one catalytic subunit. The MAP kinases ERK1 and ERK2 are important members in the tyrosine kinase pathway, in which many regulatory signals of cell growth and differentiation are transmitted. In this pathway, ERK1 and ERK2 activated by the proto-oncogene products Ras and Raf, phosphorylate the next transmitters in the signal cascade, the transcription factors and the membrane proteins, in order to transmit certain signals. Therefore it has been suggested that ERKs could be potential therapeutic targets for cancer or Alzheimer's disease, because of their function. For activation of the enzyme, two essential amino acids in ERK2, Tyr 185 and Thr 183, need to be phosphorylated by a dual specificity kinase which functions both as a tyrosine kinase and as a serine-threonine kinase. When the two amino acids are phosphorylated, the activity is maximal. If only one of the amino acids is phsophorylated, less than 1 percent of the maximum activity is observed. ERK2 can be inactivated by some phosphatases.
Following the phosphorylated- (activated-) structure, the structure of the unphosphorylated- (inactivated-) ERK2 was determined. By comparing these two structures, the conformational changes accompanying ERK2 activation were revealed. In the inactive form, the two domains of ERK2 rotate by about 15 degree relative to each other. As a result, the two domains are further apart from each other than they are in the active form. Moreover, the access of the substrate, which is phosphorylated by ERK2, to the binding site is blocked by the unphosphorylated-Tyr 185. Thus, it is revealed that both global, the domain rotations, and local, blocking of the substrate binding-site, conformational changes are involved in the activation of ERK2.
Protein Data Bank (PDB)
Zhang, F. Strand, A. Robbins, D. Cobb, M.H. Goldsmith, E.J.; "Atomic structure of the MAP kinase ERK2 at 2.3 Angstroms resolution."; Nature; (1994) 367:704-711 PubMed:8107865.
author: Yuko Tsuchiya