PEX2:PEX10:PEX12 monoubiquitinates PEX5L at cysteine-11

The RING-type E3 ubiquitin ligase sub-complex PEX2:PEX10:PEX12 catalyzes the transfer of ubiquitin from an E2-ubiquitin conjugate (one of Ub:UBE2D1, Ub:UBE2D2, or Ub:UBE2D3) to the cysteine-11 residue of the substrate PEX5L, the peroxisomal matrix protein shuttling receptor (Carvalho et al. 2007; Grou et al. 2008, Okumoto et al. 2011, Sargent et al. 2016, inferred from yeast in Dodt and Gould 1996). In contrast to PEX5, PEX7 transiently associated with the docking and translocation module (which comprises PEX14, PEX13, PEX2, PEX10, and PEX12) is not ubiquitinated. The thiol ester bond between ubiquitin and the cysteine residue of PEX5 is unusual among ubiquitin substrates, which usually have isopeptide bonds between ubiquitin and a lysine residue. Monoubiquitination of PEX5 at cysteine-11 is an integral and mandatory step in the PEX5-mediated peroxisomal protein transport pathway; in its absence, PEX5 and PEX7 cannot be extracted from the peroxisomal membrane docking-translocation machinery (the peroxisomal protein translocon), and thus transport of newly synthesized peroxisomal matrix proteins to the organelle matrix stops (Grou et al. 2009). In addition to monoubiquitinating PEX5 during peroxisomal protein import, the PEX2:PEX10:PEX12 sub-complex has also been implicated in pexophagy, a type of selective autophagy targeting peroxisomes. Pexophagy seems to be triggered mainly by ubiquitination of PEX5, which, in this case, can occur either at its cysteine-11 or lysine-209 residues, but ubiquitination of ABCD3 (also known as PMP70) and other peroxisomal membrane proteins may also be involved (Zhang et al. 2015, inferred from mouse in Nordgren et al. 2015, Sargent et al. 2016).

RING型E3泛素连接酶亚复合物PEX2:PEX10:PEX12催化泛素从E2-泛素连接物（包括Ub:UBE2D1、Ub:UBE2D2或Ub:UBE2D3之一）转移到底物PEX5L的半胱氨酸-11残基上，PEX5L为过氧化物酶体基质蛋白穿梭受体（Carvalho等，2007；Grou等，2008，Okumoto等，2011，Sargent等，2016，由Dodt和Gould，1996年的酵母实验推断）。与PEX5不同，暂时与对接和转位模块（包括PEX14、PEX13、PEX2、PEX10和PEX12）相关的PEX7并未发生泛素化。泛素与PEX5的半胱氨酸残基之间的硫酯键在泛素底物中是独特的，因为泛素通常与赖氨酸残基之间形成异肽键。在PEX5介导的过氧化物酶体蛋白转运途径中，PEX5在半胱氨酸-11位的单泛素化是一个不可或缺的步骤；其缺失将导致PEX5和PEX7无法从过氧化物酶体膜对接-转位装置（过氧化物酶体蛋白转位酶）中提取，从而停止将新合成的过氧化物酶体基质蛋白转运至细胞器基质（Grou等，2009）。除了在过氧化物酶体蛋白摄取过程中单泛素化PEX5外，PEX2:PEX10:PEX12亚复合物还与pexophagy（一种针对过氧化物酶体的选择性自噬）有关。pexophagy似乎主要由PEX5的泛素化触发，此时泛素化可发生在其半胱氨酸-11位或赖氨酸-209位，但ABCD3（也称为PMP70）和其他过氧化物酶体膜蛋白的泛素化也可能参与其中（Zhang等，2015，由Nordgren等，2015年和Sargent等，2016年的小鼠实验推断）。