Proteome complexity and the forces that drive proteome imbalance

Abstract

Summary The cellular proteome is a complex microcosm of structural and regulatory networks that requires continuous surveillance and modification to meet the dynamic needs of the cell. It is therefore crucial that the protein flux of the cell remains in balance to ensure proper cell function. Genetic alterations that range from chromosome imbalance to oncogene activation can affect the speed, fidelity and capacity of protein biogenesis and degradation systems, which often results in proteome imbalance. An improved understanding of the causes and consequences of proteome imbalance is helping to reveal how these systems can be targeted to treat diseases such as cancer.

Assembly and Function of Heterotypic Ubiquitin Chains in Cell-Cycle and Protein Quality Control

“…A large fraction of HSP70 and HSP90 clients are newly synthesized proteins that fail to fold upon release from ribosomes (Balchin et al, 2016; Brandman and Hegde, 2016; Harper and Bennett, 2016). Proteins that have not reached their native conformation even after multiple attempts of chaperone-assisted folding are rapidly degraded by the ubiquitin-proteasome system (Wang et al, 2015a; Wang et al, 2013).…”

“…These findings place K11/K48-linked chains at the heart of cell cycle and protein quality control, two conditions that rely on high proteasome activity: while the APC/C ensures that a large number of substrates are turned over during the short time span of mitosis (Sivakumar and Gorbsky, 2015), translation-coupled quality control triages up to 15% of newly synthesized proteins (Balchin et al, 2016; Harper and Bennett, 2016; Wang et al, 2015a; Wang et al, 2013). Even though the architecture of K11/K48-branched chains differs during mitosis and quality control (Figure 7E), physiological and biochemical evidence suggests that both types of K11/K48- branched chains afford a higher affinity towards the proteasome and its associated segregase p97/VCP than homotypic K11- or K48-linked conjugates (Meyer and Rape, 2014).…”

“…Posttranslational modification with the highly conserved and essential protein ubiquitin controls cell division, differentiation, and survival in all eukaryotes (Harper and Bennett, 2016; Husnjak and Dikic, 2012; Ravid and Hochstrasser, 2008; Skaar et al, 2013; Yau and Rape, 2016). The precision and versatility of ubiquitylation in signal transduction depends on the ability of cells to assemble multiple conjugates with distinct topologies and functions.…”

Co-translation drives the assembly of mammalian nuclear multisubunit complexes

“…We also show that the position of the heterodimerization domain in a protein could guide its co-translational assembly either by "sequential" or "simultaneous" pathways. These mechanisms could play an important role in maintaining cellular health as excess orphan protein subunits can overburden protein folding and quality control machineries 35 . There is a strong correlation between the amino acid sequence of a protein, its translation rate and co-translational folding 36 .…”

Guard the guardian: A CRL4 ligase stands watch over histone production

“…31,38 Together, CRLs form roughly 200 distinct ubiquitin ligases, thus accounting for up to one third of the predicted human E3 pool. 20,28 The impact of CRL4s on cellular fitness has recently been highlighted in a human genome-wide CRISPR/Cas9 knockout screen in which the constitutive CRL4 component Ddb1 scored as an essential gene. 21 At present only a handful of CRL4s have been mechanistically and structurally analyzed (see below for more details on the function of selected complexes), and thus the bulk of forecasted DCAFs WDR23 ligase activates histone mRNA processing by monoubiquitinating SLBP.…”