Figure 3

Kelch proteins act as a substrate specific adaptors for E3-ubiquitinin protein complex. (A) Cullin3 complex is Nedd8 (N8) modified and recruits E2-bound ubiquitin through RING-finger protein Rbx1. The assembly of a functional ubiquitination complex requires the binding of Cul3-E2 complex to substrate specific Kelch adaptor proteins. Cul3 directly binds to N-terminal BTB domain of Kelch protein and this E3-ubiquitination complex interacts with substrates (for example, S1, S2, S3) by C-terminal Kelch-repeat containing domains of Kelch proteins, causing ubiquitination of the target proteins and subsequent degradation (or stabilization and so on) by the proteasome system. This results in normal protein turnover of proteins required for normal functioning of muscle resulting in healthy skeletal muscles. (B) The deficiency of Kelch proteins (such as disease causing KLHL9, KLHL40, KLHL41, and KBTBD13) prevents the assembly of functional Cullin3 ubiquitination complex thereby perturbing the protein turnover process. In the model shown here, this results in accumulation of abnormal proteins (for example, S1, S2, S3) leading to unavailability of normal proteins in skeletal muscle leading to a diseased state.