Intrinsically Unstructured Proteins: Re-assessing the Protein Structure-Function Paradigm

• Central dogma of structural biology: a folded protein structure is necessary for biological function (pg 321)
• But not all biologically functional proteins encoded by genomes fold spontaneously into stable globular structures (pg 322)
• disorder can be local or global for the protein (pg 322)
• disordered regions characterized by low sequence complexity, amino acid compositional bias, and high predicted flexibility (pg 322)
• determining the structure/lack of structure of non-globular protein sequences in genomes a major challenge for structural biology (pg 322)

• in spectroscopic experiments, there are proteins that appear to be unfolded or partly folded under normal conditions in the cell (pg 323)

• evidence that many activation domains fold only upon binding their protein targets (pg 323)
• intrinsic structural disorder appears to be a common property of transcriptional activation domains (pg 324)

• inducible or constitutive binding behavior directly reflects the intrinsic secondary structural tendencies of individual protein domains (pg 325)

• rapid turnover of some of cell cycle regulation proteins (facilitated by their unstructured state in the absence of appropriate ligands) is a means of ensuring the sensitivity of the cell cycle to external conditions (pg 326)

• unfolded states have a functional role in a protein associated with transport through membranes, and membrane transport of proteins is an example of mechanisms where the cell accomplishes a goal by manipulating the protein structure (pg 326)

• question: how can unfolded proteins survived in the cell and successfully avoid protein degradation machinery long enough to perform their functions (pg 327)

• it's possible a shorter life time for unfolded cellular components may constitute part of the regulation of these proteins, supported by the roles they play in cell cycle regulation and transcriptional and translational processes (pg 327)

• functions like signaling can be achieved by linear sequences, simple sequence patterns, or isolated secondary structural motifs, so intrinsically unstructured proteins can offer several advantages in systems involved with cellular signaling and regulation, because they are inherently flexible and their local and global structures can be shaped by their environment, which might allow a single protein to recognize a large number of biological targets without sacrificing specificity (pg 327)
• the requirement for a folding transition upon binding the disordered protein domain to its target can contribute to the specificity of molecular recognition. The free energy expended to induce a folding transition reduces the overall free energy of the complex formation, so that high affinity binding can only occur when the complementary of the target is maximal; the thermodynamical balance means binding can be regulated by cellular signals or interactions with other components of cellular machinery (pg 328)

• binding affinity of an unstructured protein can also be regulated by folding transitions induced by interactions with other proteins or nucleic acids in a multimeric complex (pg 328)