Physicochemical principles that regulate the competition between functional and dysfunctional association of proteins

Abstract

To maintain protein homeostasis, a variety of quality control mechanisms, such as the unfolded protein response and the heat shock response, enable proteins to fold and to assemble into functional complexes while avoiding the formation of aberrant and potentially harmful aggregates. We show here that a complementary contribution to the regulation of the interactions between proteins is provided by the physicochemical properties of their amino acid sequences. The results of a systematic analysis of the protein-protein complexes in the Protein Data Bank (PDB) show that interface regions are more prone to aggregate than other surface regions, indicating that many of the interactions that promote the formation of functional complexes, including hydrophobic and electrostatic forces, can potentially also cause abnormal intermolecular association. We also show, however, that aggregation-prone interfaces are prevented from triggering uncontrolled assembly by being stabilized into their functional conformations by disulfide bonds and salt bridges. These results indicate that functional and dysfunctional association of proteins are promoted by similar forces but also that they are closely regulated by the presence of specific interactions that stabilize native states.protein aggregation ͉ protein complexes ͉ protein interfaces ͉ physicochemical properties

Mechanisms of protein oligomerization, the critical role of insertions and deletions in maintaining different oligomeric states

“…The effect of these regions is similar to the role of "gatekeeping" residues preventing nonspecific aggregation (41,51). Disabling regions prevent any aggregation or association with other partners and might be specific in the sense of preventing the participation in nonspecific functional pathways assisting the functional separation of paralogs.…”

“…Unlike amino acid composition analysis the aggregation propensity calculations take into account the residue context, the presence of specific patterns of alternating hydrophobic and hydrophilic residues, and residue charges. A recent study by Pechmann et al (41) reported that interfaces of protein complexes are more prone to aggregate than surface. Consistent with this study we found similar trends for homooligomers (Wilcoxon signed-rank test p-value < 10e−10, Fig.…”

Systematic interaction network filtering identifies CRMP1 as a novel suppressor of huntingtin misfolding and neurotoxicity

“…Second, disease-causing mutations can lead to perturbations in the PPI networks in affected tissues, thereby influencing pathogenesis. Changes in functional protein interactions are frequently linked to changed protein levels in cells; both phenomena have been shown to favor spontaneous protein misfolding and are indicators that a protein might influence HTT aggregation and HD pathogenesis (Pechmann et al 2009;Vavouri et al 2009). Therefore, we reasoned that HTT interaction partners displaying abnormal changes in abundance in regions of the brain that are particularly vulnerable to HD may be disease-relevant modifiers that influence mutant HTT misfolding and aggregation.…”

Understanding Gene Duplication Through Biochemistry and Population Genetics

“…Even among the binding interface residues that contribute to the binding affinity, the degree of amino acid sensitivity between similar amino acids is unclear. It has been suggested that a small subset of electrostatic residues may drive specificity in a sea of hydrophobic interactions driving affinity (Pechmann et al, 2009). Changes in untranslated regions can also affect mRNA stability, but have not been factored into the view described above.…”