High impact information on PEX12

• PEX12 encodes an integral membrane protein of peroxisomes [1].
• Overexpression of either PEX5 or PEX10 can suppress this PEX12 mutation, providing genetic evidence that these interactions are biologically relevant [2].
• Using two-hybrid studies, blot overlay assays, and coimmunoprecipitation experiments, we observed that the zinc-binding domain of PEX12 binds both PEX5, the PTS1 receptor, and PEX10, another integral peroxisomal membrane protein required for peroxisomal matrix protein import [2].
• Mutations in human PEX12 result in Zellweger syndrome, a lethal neurological disorder, and implicate the zinc ring domain in PEX12 function [2].
• Furthermore, we identified a patient with a missense mutation in the PEX12 zinc-binding domain, S320F, and observed that this mutation reduces the binding of PEX12 to PEX5 and PEX10 [2].

Biological context of PEX12

• However, one patient who presented relatively mild clinical and cellular phenotypes was a compound heterozygote for two seemingly severe mutations on each PEX12 allele [3].
• Transfection studies confirmed the expression of similarly sized PEX12 proteins from the PEX12/c.26,27Delta allele [3].
• A comparison between PEX12 genotypes and the clinical and cellular phenotypes of the corresponding PBD patients suggests a relatively straightforward relationship between genotype and phenotype in this group of the PBDs, such that the loss of PEX12 function leads to more-severe cellular and clinical phenotypes [3].
• A stable transformant of ZP109 with the PEX12 was morphologically and biochemically restored for peroxisome biogenesis [4].
• Two unrelated patients of this group manifesting peroxisome deficiency disorders possessed homozygous, inactivating PEX12 mutations: in one, Arg180Thr by one point mutation, and in the other, deletion of two nucleotides in codons for 291Asn and 292Ser, creating an apparently unchanged codon for Asn and a codon 292 for termination [4].

Anatomical context of PEX12

• The N-terminal region of Pex12p, including amino acid residues at positions 17-76, was required for localization to peroxisomes, while the sequence 17-76 was not sufficient for peroxisomal targeting [5].
• GFP fusions of T. cruzi PEX10 and L. major PEX12 also localized to glycosomes in T. brucei indicating that glycosomal membrane protein targeting is conserved across trypanosomatids [6].
• METHODS: Measurement of beta-oxidation enzymes, peroxisomal biochemical analysis in body fluids and cultured skin fibroblasts, and DNA analysis of the PEX12 gene were performed [7].
• PEX12, the pathogenic gene of group III Zellweger syndrome: cDNA cloning by functional complementation on a CHO cell mutant, patient analysis, and characterization of PEX12p [4].

Physical interactions of PEX12

• The RING finger of Pex12p bound to Pex10p and the PTS1-receptor Pex5p [5].
• PEX12 interacts with PEX5 and PEX10 and acts downstream of receptor docking in peroxisomal matrix protein import [2].

Other interactions of PEX12

• Moreover, Pex12p was co-immunoprecipitated with Pex10p from CHO-K1 cells, where Pex5p was not associated with the Pex12p-Pex10p complex [5].
• These and other results lead us to propose that PEX12 and PEX10 play direct roles in peroxisomal matrix protein import downstream of the receptor docking event [2].
• Pex5p carrying the cargos, PTS1 and PTS2, docks with the initial site Pex14p in a putative import machinery, subsequently translocating to other components such as Pex13p, Pex2p, Pex10p and Pex12p, whereby the matrix proteins are imported [8].
• The authors found that the patient had a peroxisome biogenesis disorder caused by mutations in the PEX12 gene, although all peroxisomal functions in cultured skin fibroblasts were normal [7].

References