MAP kinase-activated protein kinase 2 (MK2) is an enzyme that in humans is encoded by the MAPKAPK2 gene. MAP kinase-activated protein (MAPKAP) kinase 2 is one of two known protein kinases that can be phosphorylated and activated by MAP kinase. Here we introduce the first complete primary structure of MAPKAP kinase 2 elucidated from human cDNA sequences. Sequence analysis showed that MAPKAP kinase 2 is a 370 amino acid protein with a proline-rich N-terminal region and a conserved catalytic domain. Northern blot analysis of MAPKAP kinase 2 revealed 4.8 kb mRNA species in HL-60 cells. In addition, we show the first evidence that recombinant MAPKAP kinase 2 is phosphorylated and activated by MAP kinase in vitro.
Figure 1. Protein structure of MK2.
Functions
This gene encodes a member of the Ser/Thr protein kinase family. This kinase is regulated by direct phosphorylation of p38 MAP kinase. It is known that this kinase in combination with p38 MAP kinase can participate in many cellular processes, including stress and inflammatory responses, nuclear export, regulation of gene expression and cell proliferation. The heat shock protein HSP27 has been shown to be one of the substrates for this kinase in vivo. Two transcript variants of the gene have been found to encode two different subtypes.
Structure and function of MK2
MK2 belongs to the serine-threonine protein kinase family. It was originally discovered as an extracellular regulatory protein kinase and can phosphorylate heat shock protein 27 and mouse homologous heat shock protein 25 (HSP25); later research It was found that MK2 is mainly activated by phosphorylation of p38MAPK and is one of the downstream substrates of p38. MK2 is a primary sequence consisting of 400 amino acids. It consists of a proline-rich N-terminal region (amino acids 10-40, a region with MAPK characteristics), a protein kinase catalytic domain (amino acids 64-325), and a regulatory structure. Domain (amino acids 328-364) and a C-terminal domain (amino acids 366-390, representing the binding site of p38MAPK, also known as the docking region). The C-terminus has a two-component nuclear localization signal (NLS, amino acids 371-374; 385-389 sequence), which mainly maintains the position of MK2 in the nucleus of the cell in the resting state; instead, the nuclear output signal The export signal (NES, amino acids 356-365) is located between the N-terminus and the NLS domain and triggers nuclear export sequences upon activation of MK2. In resting cells, p38MAPK and MK2 form a complex in the nucleus, and activated NLS fixes it in the nucleus. When cell stress causes p38 upstream kinase activation to cause p38MAPK phosphorylation, such as mitogen-activated protein kinase kinase 3/6 (mitogen-activated protein kinase kinase 3/6, MKK3 / 6), activated p38MAPK phosphorylates Thr222 on MK2, Ser272 and Thr334 loci. When the Thr334 site is activated, NES is exposed, and the p38MAPK-MK2 complex is translocated to the cytoplasm, activating its downstream substrate. At the same time, activation of the Thr222 site in the kinase domain activation loop plays a key role in MK2-dependent downstream substrate activation, including activation of enzymes, activation of proteins that regulate cytoskeletal movement, activation of mRNA-binding proteins, cell cycle and apoptosis regulation Factors, etc.
Applications
As a downstream target of p38MAPK signaling pathway, MK2 participates in the occurrence and development of various cardiovascular diseases. Based on MK2's extensive action pathway, MK2 has become a potential drug target for the treatment of some diseases. The MK2 inhibitor that competitively blocks its downstream pathway by binding to the ATP binding site mainly has the following problems: First, the ATP binding site of MK2 and MK3, MK5, protein kinase A, cyclin-dependent kinase 2, etc. The binding sites of some kinases are similar, which greatly affects their selectivity, and the crystal structure of MK2 has a deep and narrow pocket shape in the ATP binding site. Some small flat compounds can be well accommodated in ATP Binding in the pocket but its structure is difficult to modify to improve kinase selectivity and affinity; secondly, the high intracellular ATP level and the high affinity of MK2 for ATP lead to the low biological effectiveness of small molecule ATP competitive MK2 inhibitors efficiency (BE), so increasing the biological efficiency of ATP-competitive MK2 inhibitors remains a challenge. Solubility, permeability, poor selectivity, and cell viability are the key issues that ATP competitive MK2 inhibitors need to address.
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