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Structural Research of Membrane-Bound Metalloproteases

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Membrane-bound metalloproteases have various functions such as protein hydrolysis, degradation and remodeling of extracellular matrix, and intracellular signal transduction. Most of them contain zinc-bound metalloprotease domains. By regulating signal transduction and tumor microenvironment, it participates in pathological processes including tumor occurrence, development, invasion, and metastasis. Therefore, deeper research into the function of membrane-bound metalloproteases in cancer immune regulation will help develop cancer diagnosis and immunotherapy methods.

Structure and action mechanism of Escherichia coli zinc metalloprotease RseP

RseP from Escherichia coli is a zinc metalloprotease site 2 protease (S2P) homolog. It participates in the second step of signal transduction by sequentially cleaving type II membrane proteins. The Ec RseP structure contains three C-terminal residues. TM1 contains two zinc coordination His residues. TM3 is divided into two segments by a circular protrusion. Ec RseP is expected to have two inner membranes β Hairpin (the C1N loop and MREβ-loop), located between TM1 and TM2.

Two views of the full-length Ec RseP structure. Figure 1. Two views of the full-length Ec RseP structure. (Yuki Imaizumi, et al., 2022)

Structure Mycobacterium tuberculosis M13 metalloprotease Zmp1

Zmp1 is a type II transmembrane protein with a short N-terminal intracellular structural domain, a transmembrane helix, and a protease structural domain localized in extracellular or intracellular vesicles. It has D1 and D2 structural domains, both consisting of helices. Two open-state cryo-EM structures of Zmp1 have been reported at 3.1 Å and 4.6 Å resolution, and the dominant state in solution is revealed by SAXS analysis.

Cryo-EM maps of Zmp1. Figure 2. Cryo-EM maps of Zmp1. (Liang WG, et al., 2021)

Protein Organism Method Resolution PDB Entry ID
PRO form of proMMP-7 in complex with zwitterionic membrane Homo sapiens SOLUTION NMR / 2MZH
PRO form of proMMP-7 in complex with anionic membrane Homo sapiens SOLUTION NMR / 2MZI
M1 zinc metallopeptidase E323A mutant Deinococcus radiodurans R1 X-ray diffraction 1.83 Å 6IFF
M1 zinc metallopeptidase E323A mutant bound to Tyr-ser-ala substrate Deinococcus radiodurans R1 X-ray diffraction 1.9 Å 6IFG
Two domain M1 Zinc metallopeptidase E323A mutant bound to L-tryptophan amino acid Deinococcus radiodurans R1 X-ray diffraction 2.35 Å 6KOY
Partial open state of zinc metalloprotease 1 Mycobacterium tuberculosis H37Rv X-ray diffraction 4.6 Å 7K1V
RseP orthologue in complex with batimastat in space group P21 Kangiella koreensis DSM 16069 X-ray diffraction 3.15 Å 7W6Z
PDZ-C domain fragment of RseP orthologue Kangiella koreensis DSM 16069 X-ray diffraction 1.15 Å 7W70
Zinc metalloprotease zmp1 in open state Mycobacterium tuberculosis H37Rv X-ray diffraction 3.1 Å 6XLY
Insulin-regulated aminopeptidase with alanine in active site Homo sapiens X-ray diffraction 3.02 Å 4P8Q
Insulin-regulated aminopeptidase with lysine in active site Homo sapiens X-ray diffraction 2.96 Å 4PJ6
Insulin-regulated aminopeptidase in complex with ligand Homo sapiens X-ray diffraction 3.31 Å 4Z7I
Insulin regulated aminopeptidase Homo sapiens X-ray diffraction 3.37 Å 5C97
Insulin-regulated aminopeptidase complexed with a macrocyclic peptidic inhibitor Homo sapiens X-ray diffraction 3.2 Å 6YDX
Aminopeptidase N Escherichia coli X-ray diffraction 1.5 Å 2DQ6
Aminopeptidase N complexed with bestatin Escherichia coli X-ray diffraction 1.6 Å 2DQM
Aminopeptidase N Neisseria meningitidis MC58 X-ray diffraction 2.05 Å 2GTQ
PepN (Aminopeptidase N)in complex with Bestatin Escherichia coli K-12 X-ray diffraction 2.3 Å 2HPT
Aminopeptidase N in complex with arginine Escherichia coli K-12 X-ray diffraction 2 Å 3B2P
Aminopeptidase N in complex with Lysine Escherichia coli X-ray diffraction 1.5 Å 3B2X

Table 1. Structural research of membrane-bound metalloproteases.

To study the structure of membrane proteins, we use NMR spectroscopy, cryo-electron microscopy (cryo-EM) and X-ray crystallography. Structural analysis of membrane-bound metalloproteases contributes to the development of novel antimicrobial targets and cancer therapies.

Creative Biostructure has long been committed to the study of structural biology and membrane proteins. Our experts have extensive experience in determining the structure of membrane proteins. If you are interested in our services, please contact us and we will provide you with a professional and comprehensive solution.

References

  1. Yuki Imaizumi, et al. Mechanistic insights into intramembrane proteolysis by E. coli site-2 protease homolog RseP. Sci. Adv. 2022. 8, eabp9011.
  2. Liang WG, et al. Structural analysis of Mycobacterium tuberculosis M13 metalloprotease Zmp1 open states. Structure. 2021. 29(7):709-720.

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