Recently, researchers from the School of Life Sciences of Tsinghua University published a paper entitled "Structure of a presenilin family intramembrane aspartate protease", which reported the crystal structure of an aspartic protease in the presenilin / SPP family membrane. In the "Nature" magazine on the 19th.
The corresponding author of the article is Professor Shi Yigong, Dean of the School of Life Sciences, Tsinghua University. His research team is mainly dedicated to the study of molecular mechanisms of tumorigenesis and apoptosis using structural biology and biochemistry. This is another important achievement of this research group in the field of structural biology research. Regulated intramembrane proteolysis (RIP) is a new signaling mechanism discovered in recent years, that is, transmembrane proteins can be cleaved in their transmembrane regions and release their cytoplasmic parts, which then enters the nuclear control Gene transcription. The RIP protein adopts a conservative model in a wide range of organisms from bacteria to humans. So far, there are three protease families involved in RIP, including metalloproteinase S2P (site-2 protease); aspartic protease presenilin (PS) family and signal peptide peptidase family (SPP); serine protease rhomboid family. Substrates of the aspartic protease PS family include Amyloid precursor protein (APP) and plasma membrane receptor Notch.
Neurobiological studies have proved that one of the important pathogens causing Alzheimer's disease is the accumulation of Î²-Amyloid (AÎ²) polypeptide. AÎ² comes from APP. APP undergoes several shears to finally produce AÎ², of which two-step shearing (Î² and Î³) is performed within the cell membrane, and the protein that performs this intramembrane shearing is a membrane-integrating protease called Î³-secretase . Unlike other membrane-integrating proteases, Î³-secretase is not a single subunit protein, but consists of four subunits, including Presenilin, Aph-1, Pen-2, and Nicastrin. Presenilin is the subunit where the active site of Î³-secretase is located and plays a central role in the Î³-secretase complex. More than 150 pathogenic presenilin mutations have been identified in the current study.
Recent structural studies of rhomboid and S2P21 prokaryotic homologues have promoted our understanding of the mechanism of these membrane embedded proteases. In contrast, the study of detailed structural information for presenilin and SPP has progressed slowly. The preferential structural information obtained by Î³-secretase complex electron microscopy analysis, presenilin CTF nuclear magnetic resonance analysis, and the crystal structure of GXGD peptidase FlaK26 was not found to have sequence homology with presenilin / SPP.
In this new article, the researchers report the crystal structure of the presenilin / SPP homolog (PSH) from Mesosporus marnii JR1 from the Black Sea. This protease includes 9 transmembrane domains (TMs), using a previously unreported protein folding method. Its amino (N) terminal region is composed of TM1â€“6, forming a horseshoe-shaped structure, surrounding the carboxyl (C) terminal region composed of TM7â€“9. The two catalytic aspartate residues are located on the cytoplasmic side of TM6 and TM7 and are close to each other in space. Water molecules approach the catalytic aspartate through a large pocket between the N-terminal and C-terminal regions. Biocom
Through this structural analysis, the researchers gained knowledge of the prosenilin / SPP family membrane proteases. This provides an important framework for a deeper understanding of the structure and mechanism of presenilin, Î³-secretase, and SPP in the future.
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