Molecular evolution of proadrenomedullin N-terminal 20 peptide (PAMP): evidence for gene co-option.
Posttranslational processing of proadrenomedullin generates two biologically active peptides, adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP). Sequence comparison of homologous proadrenomedullin genes in vertebrate evolution shows a high degree of stability in the reading frame for AM, whereas PAMP sequence changes rapidly. Here we investigate the functional significance of PAMP phylogenetic variation studying two of PAMP's better characterized physiological activities, angiogenic potential and antimicrobial capability, with synthetic peptides carrying the predicted sequence for human, mouse, chicken, and fish PAMP. All tested peptides induced angiogenesis when compared with untreated controls, but chicken and fish PAMP, which lack terminal amidation, were apparently less angiogenic than their human and mouse homologs. Confirming the role of amidation in angiogenesis, Gly-extended and free acid variants of human PAMP produced responses similar to the natural nonamidated peptides. In contrast, antimicrobial activity was restricted to human PAMP, indicating that this function may have been acquired at a late time during the evolution of PAMP. Interestingly, free acid human PAMP retained antimicrobial activity whereas the Gly-extended form did not. This fact may reflect the need for maintaining a tightly defined structural conformation in the pore-forming mechanism proposed for these antimicrobial agents. The evolution of PAMP provides an example of an angiogenic peptide that developed antimicrobial capabilities without losing its original function.
Department of Neuroanatomy and Cell Biology, Instituto Cajal, Consejo Superior de Investigaciones Científicas, Avenida Doctor Arce 37, 28002 Madrid, Spain. amartinez@cajal.csic.es
Alfredo
A
Martínez
José Antonio
JA
Bengoechea
Frank
F
Cuttitta
D015057:1-Naphthylamine / Q000031:analogs & derivatives / Q000378:metabolism; D053607:Adrenomedullin; D000818:Animals; D002645:Chickens; D019143:Evolution, Molecular; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D009389:Neovascularization, Pathologic; D016366:Open Reading Frames; D010455:Peptides / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000378:metabolism
D010455:Peptides; D011498:Protein Precursors; D011506:Proteins; C088633:proadrenomedullin; D053607:Adrenomedullin; C005444:N-phenyl-1-naphthylamine; D015057:1-Naphthylamine