Intrinsically disordered protein

Abstract

Proteins can exist in a trinity of structures: the ordered state, the molten globule and the random coil. Five examples follow which suggest that native protein structure can correspond to any of the three states (not just the ordered state) and that protein function can arise from any of the three states and their transitions. 1. In a process that likely mimics infection, fd phage converts from the ordered into the disordered molten globular state. 2. Nucleosome hyperacetylation is crucial to DNA replication and transcription; this chemical modification greatly increases the net negative charge of the nucleosome core particle. We propose that the increased charge imbalance promotes its conversion to a much less rigid form. 3. Clusterin contains an ordered domain and also a native molten globular region. The molten globular domain likely functions as a proteinaceous detergent for cell remodeling and removal of apoptotic debris. 4. In a critical signaling event, a helix in calcineurin becomes bound and surrounded by calmodulin, thereby turning on calcineurin's serine/threonine phosphatase activity.Locating the calcineurin helix within a region of disorder is essential for enabling calmodulin to surround its target upon binding. 5. Calsequestrin regulates calcium levels in the sarcoplasmic reticulum by binding about 50 ions/molecule. Disordered polyanion tails at the carboxy terminus bind many of these calcium ions, perhaps without adopting a unique structure. In addition to these examples, 16 more proteins with native disorder will be discussed. These disordered regions include molecular recognition domains, protein folding inhibitors, flexible linkers, entropic springs, entropic clocks and entropic bristles.Motivated by such examples of intrinsic disorder, we are studying the relationships between amino acid sequence and order/disorder, and from this information we are predicting intrinsic order/disorder from amino acid sequence.The sequence/structure relationships indicate that disorder is an encoded property, and the predictions strongly suggest that proteins in nature are much richer in intrinsic disorder than are those in the Protein Data Bank. Recent predictions on 29 genomes indicate that proteins from eucaryotes apparently have more intrinsic disorder than those from either bacteria or archaea, with typically > 30 % of eucaryotic proteins having disordered regions of length = 50 consecutive residues.

Flavors of protein disorder

“…where n 1 and n 2 are the number of examples from both samples, P j (1) , P j (2) , and P j (12) , are frequencies of amino acid j in both samples and in the joint sample, S 1 ϩ S 2 . In Table VII we show values of D-statistics between the three flavors of the disordered residues and the ordered residues.…”

“…8,9 More recently, such proteins have been called "natively unfolded," 10 "intrinsically unstructured," 1 and "intrinsically disordered." 2 The failure to self-fold into specific 3-D structure is likely encoded by the amino acid sequence 11 and, furthermore, regions lacking specific 3-D structure have so far been associated with 28 distinguishable functions, ranging from DNA binding to display of sites for phosphorylation to preventing interactions by means of excluded volume effects. 12 A disordered protein or a disordered region lacks specific tertiary structure and is comprised of an ensemble made up of members with distinct and usually dynamic Ramachandran angles.…”

A pre-structured helix in the intrinsically disordered 4EBP1

“…4,5 A disorder to order transition and coupled folding and binding are common terms describing IDP-target binding. 2,[8][9][10] These terms, however, mostly refer to a global topological change occurring in IDPs upon target binding. At an atomistic level an induced fit (IF) mechanism involving a coil -helix transition was proposed at the dawn of the IDP research arguing that any pre-structuring of the target-binding segment is unnecessary for binding.…”

“…At an atomistic level an induced fit (IF) mechanism involving a coil -helix transition was proposed at the dawn of the IDP research arguing that any pre-structuring of the target-binding segment is unnecessary for binding. [8][9][10][11] However, a coil -helix structural transition is not likely to occur if a targetbinding segment in a free IDP is already pre-structured in a conformation that presages its target-bound conformation. 6 In such a case conformational selection of the pre-structured segment by a target may be an efficient and more thermodynamically favorable event.…”

“…17 Early reports also pointed out the pre-structuring of the target-binding segments. 6,16 The human phosphoprotein 4EBP1 is the very first IDP explicitly described to be completely or ''wholly'' disordered, 8,9 which contributed critically to the formation of a coil -helix IF concept. Interestingly, this paradigmatic IDP was not re-analyzed in the context of the PreSMo concept.…”