3.4.21.93	D65A	site-directed mutagenesis of the propeptide residue, leads to reduced inhibition of mature PC1 by the separated propeptide mutant compared to the wild-type propeptide	669518	
3.4.21.93	D66A	site-directed mutagenesis of the propeptide residue, leads to reduced inhibition of mature PC1 by the separated propeptide mutant compared to the wild-type propeptide	669518	
3.4.21.93	D67A	site-directed mutagenesis of the propeptide residue, leads to increased inhibition of mature PC1 by the separated propeptide mutant compared to the wild-type propeptide	669518	
3.4.21.93	K61A	site-directed mutagenesis of the propeptide residue, leads to reduced inhibition of mature PC1 by the separated propeptide mutant compared to the wild-type propeptide	669518	
3.4.21.93	additional information	carboxyl terminus-truncated PC3 (1-638) containing the transmembrane domain is associated with lipid rafts in Neuro2A cells, while PC3 (1-616) and PC3-deltaTM lacking the transmembrane domain are not. PC3 (1-638) undergoes stimulated secretion and is colocalized with the secretory granule marker, chromogranin A, by immunocytochemistry. In contrast, PC3 (1-616) and PC3-deltaTM are constitutively secreted and primarily localized in the Golgi	688980	
3.4.21.93	additional information	concentration of progastrin in the antrum of PC1/3-null mice is elevated 3fold. Progastrin molecule is only partly cleaved at the dibasic Arg36-Arg37 site and even less at the Lys53-Lys54 site in the PC1/3-null mice	696097	
3.4.21.93	additional information	construction of an PC3 containing a 19 amino-acid transmembrane sequence, and/or a C-terminal glycosylation tag, the C-terminal extension is exposed to the endoplasmic reticulum lumen, overview	667660	
3.4.21.93	additional information	construction of PC1 prosegment, amino acids 1-110, fused to the C-terminal PC1 tail, amino acids 619-753, termed proCT construct	668621	
3.4.21.93	additional information	design of prohormone convertase-2-specific mutations into the catalytic domain of PC1/3 in order to investigate the molecular contributions of these sequences to PC1/3-specific properties. The exchange of residues RQG314 with the SY sequence present in the same location within PC2 shifts the pH optimum of PC1/3 upward into the neutral range, other mutations in the catalytic domain had no effect. None of the full-length PC1/3 mutants examined exhibits increased specific activity, but the 66-kDa form of the RQG314SY mutant is 2 to 4 times more active than the 66-kDa form of wild-type PC1/3. Mutation of GIVTDA243–248 to QPFMTDI, a molecular determinant of 7B2 binding, results in increased zymogen expression but no propeptide cleavage or secretion, suggesting that this mutant is trapped in the endoplasmic reticulum. None of the mutations examined confers PC2-specific properties. No mutant exhibits altered calcium requirements	717543	
3.4.21.93	additional information	generation of chimeric PC1-propeptide/SAAS CT peptide constructs, effects on C-terminal PC1 processing are limited to the construct containing the PC1 propeptide alone when expressed in AtT20 cells, while both the PC1 propeptide and the SAAS CT propeptide are inhibitory on C-terminal PC1 zymogen processing when expressed in HEK293 cells, overview	669648	
3.4.21.93	additional information	identification of polymorphisms of the PC1 gene in 447 individuals from three breeds. Only the P1, P2, P3, P9, and P10 loci show polymorphisms, and 12 SNPs in the PC1 gene have been identified. The polymorphisms are significantly associated with caprine body height and chest circumference	717206	
3.4.21.93	additional information	PC1/3 null mutant mice show C-terminally impaired but not completely blocked proIAPP processing, overview	668377	
3.4.21.93	additional information	PC1/3-deficient cells do not show preproGIP processing	669436	
3.4.21.93	additional information	PC1/3DELTA significantly decreases prohormone convertase 1/3 promoter activity by more than 60%. A 50% reduction when both E-boxes are mutated, even though the STAT3 sites remain intact (PC1/3DELTAE12). Mutation of both STAT3 sites (PC1/3DELTAS12) does not affect basal prohormone convertase 1/3 promoter activity, but leptin stimulation is lost. Mutating the E-box furthest from the start site (E-box 1, PC1/3DELTAE1) only has a significant effect on prohormone convertase 1/3 promoter activity under leptin stimulation, whereas mutating the E-box closest to the start site (E-box 2, PC1/3DELTAE2) has a more pronounced effect on luciferase expression with a loss of approximately 50% prohormone convertase 1/3 promoter activity levels in both leptin-stimulated and unstimulated cells	700215	
3.4.21.93	additional information	single amino acid substitution in the PC1/3 propeptide can induce significant modifications of its inhibitory profile toward its cognate enzyme	669518	
3.4.21.93	N222D	autocatalytic and neuropeptide processing is impaired	687032	
3.4.21.93	N222D	leads to obesity, abnormal proinsulin processing, reduced fecundity, impaired autocatalysis and multiple endocrinological defects in mice homozygous for the mutation. Increased energy intake, a more efficient metabolism and reduced alpha-MSH signaling contribute to the obesity. Heterozygous littermates exhibit an intermediate phenotype for both sexes, thus this mutation results in a semi-dominant phenotype	-, 687032	
3.4.21.93	N309K	naturally occuring mutation identified in four siblings presenting with congenital diarrhea and various endocrinopathies. The mutation affects the oxyanion hole transition state-stabilizing amino acid within the active site, which is critical for appropriate proprotein maturation and enzyme activity. The N309K mutant protein exhibits normal, though slowed, prodomain removal and is secreted from both HEK-293 and Neuro-2A cells. The secreted enzyme shows no catalytic activity, and is not processed into the 66 kDa form	732772	
3.4.21.93	R50A	site-directed mutagenesis of the propeptide residue, leads to increased inhibition of mature PC1 by the separated propeptide mutant compared to the wild-type propeptide	669518	
3.4.21.93	R51A	site-directed mutagenesis of the propeptide residue, leads to increased inhibition of mature PC1 by the separated propeptide mutant compared to the wild-type propeptide	669518	
3.4.21.93	R53A	site-directed mutagenesis of the propeptide residue, leads to reduced inhibition of mature PC1 by the separated propeptide mutant compared to the wild-type propeptide	669518	
3.4.21.93	R54A	site-directed mutagenesis of the propeptide residue, leads to increased inhibition of mature PC1 by the separated propeptide mutant compared to the wild-type propeptide	669518	
3.4.21.93	R62A	site-directed mutagenesis of the propeptide residue, leads to reduced inhibition of mature PC1 by the separated propeptide mutant compared to the wild-type propeptide	669518	
3.4.21.93	S307L	naturally occurring mutation (patient homozygous for the mutation). Markedly impairs catalytic activity, intracellular trafficking appears normal. Retains some autocatalytic activity, even though it is completely inactive on other substrates. Patient has obesity and persistent diarrhea, but no history of reactive hypoglycemia. Hyperphagia makes a major contribution to the obesity in this syndrome	687962	
3.4.21.93	S357G	mutant represents a prohormone convertase PC1/3 hypermorph. Mutant protein exhibits a lower calcium dependence, a higher pH optimum, and a higher resistance to peptide inhibitors than the wild-type enzyme. The mutant exhibits increased cleavage to the C-terminally truncated form, and kinetic parameters of the full-length and truncated mutant enzymes are also altered. The S357G mutation broadens the specificity of the enzyme, it displays proprotein convertase 2-like specificity on the substrate proCART, the precursor of the cocaine- and amphetamine regulated transcript neuropeptide. The mutant enzyme possesses unusual processing activity that may significantly change the profile of circulating peptide hormones	731721	
3.4.21.93	S52A	site-directed mutagenesis of the propeptide residue, unaltered inhibition of mature PC1 by the separated propeptide mutant compared to the wild-type propeptide	669518	
3.4.21.93	S52A/R53A	site-directed mutagenesis of the propeptide residues, leads to increased inhibition of mature PC1 by the separated propeptide mutant compared to the wild-type propeptide	669518