Poly-ubiquitination of target proteins through K63 has recently become the focus of intense study. The topology of this linkage type is quite different from polyubiquitin linked through lysine 48. Modification of proteins by K63-linked polyubiquitination has been implicated in, among other cellular processes, the regulation of the DNA damage response, endosomal sorting, autophagy of misfolded/aggregated proteins, and neurodegeneration. These di-ubiquitin chains are generated from the enzymatic linkage of wild-type ubiquitin through lysine 63. The most distal ubiquitin contains an arginine substitution for a lysine at position 63, limiting chain length.
