Through an unknown mechanism RING Ubox type E dimers and

Through an unknown mechanism, RING/Ubox-type E3 dimers and the N-terminal tail have been shown to function as a modulator of full E3 ubiquitin ligase activity [27]. LRSAM1 promotes a significant enhancement in the formation of the high-molecular-weight products or E3 activity when the RING domain is present in tandem with its N-terminal domain(s). SAM and CC2-SAM domains can act in a good intentions negative fashion to inhibit the function of LRSAM1 in vitro and in vivo. The CC2-SAM-mediated inhibition can be counteracted by the tandem CC1 domain rather than the individual CC1 domain. Studies showed that the coiled-coil domain played roles in regulating the self-association and the disruption of oligomerization is expected to abolish E3 activity [12]. The CC2-SAM and CC1-CC2-SAM domains will be used as a tool for further functional analysis of LRSAM1 and searching other substrates.
Conflict of interest
Acknowledgements This work is supported by the Natural Science Foundation of China (30970630 and 31270831), the Outstanding Youth Science Foundation of Chongqing (cstc2011jjjq10003), the Program for New Century Excellent Talents in University (NCET-08-0912), the Fundamental Research Funds for the Central Universities (XDJK2016C158) and the Doctoral Fund of Southwestern University (XJKJXM003338).
Introduction Skeletal muscle mass represents up to 40% of the young adult body weight. Its maintenance is regulated by the equilibrium between muscle growth or physiological hypertrophy and muscle atrophy, which is reflected on the cellular level by the balance between protein synthesis and degradation. While hypertrophy relies mainly on the activation of the Phosphatidylinositol 3-kinase and mammalian target of rapamycin (PI3K–mTOR) signaling pathway, immobilization, denervation, aging, or diseases such as cancer may induce muscle atrophy [1]. In muscle cells, the autophagy–lysosome and the ubiquitin–proteasome systems (UPSs) are the main protein degradation mechanisms [2], [3]. In particular, the UPS is responsible for the degradation of the majority of cytoplasmic proteins [4]. The UPS requires the tagging of substrates by ubiquitin via an enzymatic cascade[4], [5]. First, the E1-ubiquitin activating enzyme covalently attaches to ubiquitin through an ATP-driven step. Once activated, ubiquitin is transferred to E2-ubiquitin conjugating enzymes. The last step requires the concerted action of an E2-enzyme and an E3-ubiquitin ligase, which transfer the ubiquitin from the E2-enzyme onto the substrate. Once poly-ubiquitylated, the substrate is targeted to the proteasome for degradation. Cullin-RING (really interesting new gene) ligases (CRLs) represent the largest family of E3-ubiquitin ligases in mammalian cells[6], [7]. In order to form CRL complexes, each cullin, which forms the backbone of the E3-ligase complex, interacts modularly with RING (really interesting new gene) domain proteins Rbx1 or Rbx2 that are in turn bound to E2-enzymes. Each member of the cullin protein family binds also to a specific subset of adaptor proteins, thereby achieving specificity for a range of cellular substrates. The activity of CRL is regulated by the post-translational modification of the cullin protein with the small ubiquitin-like protein nedd8[6], [7], [8]. The essential role of CRL for adult muscle homeostasis has been unraveled by the discovery that nedd8 is almost exclusively expressed in muscles, and the discoveryof the requirement of cullin-1 and its substrate adaptor atrogin-1 (MAFbx, Fbxo32), to mediate muscle atrophy. However, while largely uncharacterized, there is an emerging role for other substrate adaptors for cullin-1 and CRL complexes that are formed by other cullin proteins, like cullin-3, for myogenesis and skeletal muscle development. In the last 20 years, the role of CRLs has been mainly investigated in the context of cancers, revealing a plethora of functions relevant for carcinogenesis[12], [13]. So far, many of the identified CRL substrates play a role in cell cycle progression, such as Cyclin E[15], [16]that is a gatekeeper of the passage from the G1 phase to the S phase. Therefore, CRL recently became an attractive potential anticancer target, and the discovery of inhibitors of cullin neddylation, such as MLN4924, opened new therapeutic avenues. MLN4924 is currently undergoing clinical trials for various cancer types[18], [19].