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When Good Proteins Go Bad… The Amyloid Precursor Protein, its Functions and Dysfunctions Caitlin “Bio Queen” Mecum Rachael “Handmaiden” Sondeno John “Wiegeabo” Victor Kirk “Keyboard Jockey” Van Gorkom CSUS Bioinformatics Winter 2002 Protein Stats Name: Amyloid Precursor Protein AKA: APP Last known location: In your brain DNA location: Chromosome 21, 11, & 19 Common Disguises (isoforms): 695, 751, 770 AA, based on alternative splicing Known Hangouts: neuronal tissue (695), other disguises are found throughout the body Convictions and Acquittals (Exons & Introns): 16 & 15, respectively May be considered armed and dangerous if you cut him wrong. TMAP Findings: Predicts transmembrane segments. APP only spans the cell membrane once. Amino acid segments 624-652 are predicted to cross the membrane threshold. GREASE Findings: Troubled Childhood (evolution) Legal Activities When on the job, APP acts as a functional neuronal receptor and communications engineer. APP plays a role in intracellular signaling by regulating cell-cell or cell-substrate interactions. As a receptor it binds to metals (Zn, Fe, Cu), clathrin, and heparin. Involved with synaptogenesis (formation and growing of new neural pathways). Past Employment (Normal Functions) Normally, APP clips itself using two different pathways, -secretase and - secretase. Following the -secretase pathway, APP is clipped between amino acids 612 and 613, or between the 16th and 17th amino acids with regards to the A protein. A full-length version of A is not formed. The -secretase pathway clips APP between amino acids 596 and 597 and is followed by a presenilin-1 regulated -secretase pathway that clips the A protein at amino acid 40. This forms a full-length A protein (A 1-40). Both - and - pathways normally do not engage in criminal activity. Most Recent Good Mugshot Most Recent Good Mugshot Criminal Activities Deviant behavior can lead to major system malfunctions. Definition: missense – a change in a codon that results in a different amino acid A mutation in the presenilin-1 gene found in FAD can lead to 42 clipping, or an A142 protein. Known as Swedish FAD missense, a mutation 2 amino acids before the normal A1-40 region can increase the likelihood of plaque formation. A Flemish-Dutch FAD missense alters the -secretase cleavage pathway which can lead to a protein more likely to aggregate. The British FAD missense involves a mutation after the normal A1-40 region which results in an abnormal A1-44. Consequences of Deviant Behavior Normal A1-40 protein formation will result in an -helical structure. However, mutated versions, especially A1-42, tend to form -sheets. These -sheets like to clump together and precipitate which can lead to the formation of plaques. Formation of plaques can also be influenced by interaction with A by metals such as aluminum, zinc, copper, and iron. References Clippingdale AB, Wade JD, Barrow CJ. Amyloid-β peptide and its role in Alzheimer’s disease. Journal of Peptide Science 2001; 7: 227-249 Coulson EJ, Paliga K, Beyreuther K, Masters, CL. What the evolution of the amyloid protein precursor supergene family tells us about its function. Neurochemistry International 2000; 36(3): 175-184. Diehlmann A., Ida N., Weggen S., Grunberg J., Haass C., Masters CL, Bayer TA, Beyreuther K. Analysis of presenilin 1 and presenilin 2 expression and processing by newly developed monoclonal antibodies. Journal of Neuroscience Research 1999; 56: 405-419. Kienlen-Campard P., Tasiaux B., Octave JN. The processing and biological function of the human amyloid precursor protein in functional synapse formation in cultured hippocampal neurons. Experimental Gerontology 2000; 35(6-7): 843850. Morimoto T, Ohsawa I, Takamura C, Ishiguro M, Kohsaka S. Involvement of amyloid precursor protein (APP): lessons from different cellular models. Journal of Neuroscience Research 1998; 51: 185-195. Biology Workbench at SDSC http://workbench.sdsc.edu NCBI Entrez at http://www.ncbi.nlm.nih.gov Tools used in the Workbench: Ndjinn, TMAP, GREASE, CLUSTALW, BLASTP, SWISSPROT JIM IS WONDERFUL! TOM IS BRILLIANT! TOM AND JIM ARE BENEVOLENT GODS OVER ALL THEIR DOMAIN.