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      Proprotein and prohormone convertases: a family of subtilases generating diverse bioactive polypeptides1Published on the World Wide Web on 17 August 1999.1

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      Brain Research
      Elsevier BV

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          Translating cell biology into therapeutic advances in Alzheimer's disease.

          D. Selkoe (1999)
          Studies of the molecular basis of Alzheimer's disease exemplify the increasingly blurred distinction between basic and applied biomedical research. The four genes so far implicated in familial Alzheimer's disease have each been shown to elevate brain levels of the self-aggregating amyloid-beta protein, leading gradually to profound neuronal and glial alteration, synaptic loss and dementia. Progress in understanding this cascade has helped to identify specific therapeutic targets and provides a model for elucidating other neurodegenerative disorders.
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            Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene.

            Human obesity has an inherited component, but in contrast to rodent obesity, precise genetic defects have yet to be defined. A mutation of carboxypeptidase E (CPE), an enzyme active in the processing and sorting of prohormones, causes obesity in the fat/fat mouse. We have previously described a women with extreme childhood obesity (Fig. 1), abnormal glucose homeostasis, hypogonadotrophic hypogonadism, hypocortisolism and elevated plasma proinsulin and pro-opiomelanocortin (POMC) concentrations but a very low insulin level, suggestive of a defective prohormone processing by the endopeptidase, prohormone convertase 1 (PC1; ref. 4). We now report this proband to be a compound heterozygote for mutations in PC1. Gly-->Arg483 prevents processing of proPC1 and leads to its retention in the endoplasmic reticulum (ER). A-->C+4 of the intro-5 donor splice site causes skipping of exon 5 leading to loss of 26 residues, a frameshift and creation of a premature stop codon within the catalytic domain. PC1 acts proximally to CPE in the pathway of post-translational processing of prohormones and neuropeptides. In view of the similarity between the proband and the fat/fat mouse phenotype, we infer that molecular defects in prohormone conversion may represent a generic mechanism for obesity, common to humans and rodents.
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              Subtilases: the superfamily of subtilisin-like serine proteases.

              Subtilases are members of the clan (or superfamily) of subtilisin-like serine proteases. Over 200 subtilases are presently known, more than 170 of which with their complete amino acid sequence. In this update of our previous overview (Siezen RJ, de Vos WM, Leunissen JAM, Dijkstra BW, 1991, Protein Eng 4:719-731), details of more than 100 new subtilases discovered in the past five years are summarized, and amino acid sequences of their catalytic domains are compared in a multiple sequence alignment. Based on sequence homology, a subdivision into six families is proposed. Highly conserved residues of the catalytic domain are identified, as are large or unusual deletions and insertions. Predictions have been updated for Ca(2+)-binding sites, disulfide bonds, and substrate specificity, based on both sequence alignment and three-dimensional homology modeling.
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                Author and article information

                Journal
                Brain Research
                Brain Research
                Elsevier BV
                00068993
                November 1999
                November 1999
                : 848
                : 1-2
                : 45-62
                Article
                10.1016/S0006-8993(99)01909-5
                de4f1db8-3f67-4d42-a2ea-8017cbcd9256
                © 1999

                http://www.elsevier.com/tdm/userlicense/1.0/

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