Requirements for presenilin-dependent cleavage of notch and other transmembrane proteins.
Ligand binding to receptors of the LIN-12/Notch family causes at least two proteolytic cleavages: one between the extracellular and transmembrane domains, and the other within the transmembrane domain. The transmembrane cleavage depends on Presenilin, a protein also required for transmembrane cleavage of beta-APP. Here, we have assayed the substrate requirements for Presenilin-dependent processing of Notch and other type I transmembrane proteins in vivo. We find that the Presenilin-dependent cleavage does not depend critically on the recognition of particular sequences in these proteins but rather on the size of the extracellular domain: the smaller the size, the greater the efficiency of cleavage. Hence, Notch, beta-APP, and perhaps other proteins may be targeted for Presenilin-mediated transmembrane cleavage by upstream processing events that sever the extracellular domain from the rest of the protein.
Struhl
G
G
Department of Genetics and Development, Howard Hughes Medical Institute, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA. struhl@cuccfa.ccc.columbia.edu
Adachi
A
A
D000595:Amino Acid Sequence; D000818:Animals; D029742:Caenorhabditis elegans Proteins; D003593:Cytoplasm; D004330:Drosophila; D029721:Drosophila Proteins; D034281:Dynamins; D005110:Extracellular Space; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D015801:Helminth Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017405:Herpes Simplex Virus Protein Vmw65 / Q000235:genetics; D007763:Lac Operon; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D053764:Presenilin-1; D017434:Protein Structure, Tertiary; D051880:Receptors, Notch; D019076:Transgenes / Q000502:physiology
D029742:Caenorhabditis elegans Proteins; D029721:Drosophila Proteins; D018840:HSP70 Heat-Shock Proteins; D015801:Helminth Proteins; D017405:Herpes Simplex Virus Protein Vmw65; C082460:Lin-12 protein, C elegans; D008565:Membrane Proteins; C497759:N protein, Drosophila; D053764:Presenilin-1; D051880:Receptors, Notch; D020558:GTP Phosphohydrolases; D034281:Dynamins