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The tale of protein disorder

Even today, when people think about the protein structures, in most cases they sees them like that:

MutT enzyme protein order
protein well ordered
MutT enzyme (pdb: 1TUM) Human pancreatic ribonuclease (pdb: 2k11)
tTNA endonuclease protein
well structured order protein
Human tRNA endonuclease SEN15 subunit (pdb: 2gw6)
Kalirin DH1 domain (pdb: 1kr9)
borring, borring, ... well defined  and static structures.

But, actually it is not true. Proteins are flexible, they can change the shape:

order disorder example protein
example order/disorder protein
protein tRNA endonuclease kalirin DH1 domain
Even better, some of them can be extremelly flexible

protein disorder example


Protein disorder at the NTD of the target T0590 (PDB id: 2kzw)


We call them intrinsically unstructured proteins (IUPs) or simply unfolded proteins or disordered proteins. The discovering of IUPs chalanged one of the main  protein structure paradigm, which states that a specific well-defined structure is required for the correct function of a protein and that the structure defines the function of the protein. This is clearly not true for intrinsically unfolded proteins that remain functional despite the lack of a well-defined structure. Such proteins, in some cases, can adopt a fixed three dimensional structure after binding to other macromolecules.  Due this intrinsic flexibility protein disorder is particularly enriched in proteins implicated in cell signaling, transcription and chromatin remodeling functions. Moreover, they are connected with many diseases (a lot of key oncogens have large unstructured regions, e.g. p53 and BRCA1, D2D2 concept).

Bellow you can few more examples of disordered proteins:


secondary structure of CASP8 disordered protein
T0556 protein disorder transition simulation protein folding by MODELLER restrains
Simulation of folding and unfolding (transition form order/disorder state for CASP8 target T0556 done using MODELLER based on predicted secondary structure and remote template (PDB id: 3dnv_B).



ss of amelogenin

amelogenin IUP protein DISPROT

Amelogenin as an example of intrinsically disordered protein. Extended, unfolded state of the protein is crucial for formation of protein-mineral interactions (generated by MODELLER with restrains for predicted secondary structure). Above the model predicted alignment with secondary structure is presented.

calmodulin protein disorder linker DISPROTprotein disorder as flexible linker calmodulin

Disorder as a flexible linker. Calmodulin with and without Ca2+ ions (based on pdb: 2f2o, 1cfd, 1cll).


Contact: Lukasz Kozlowski

If you find this site useful, please consider citing the reference:
Kozlowski LP, Bujnicki JM. MetaDisorder: a meta-server for the prediction of intrinsic disorder in proteins. BMC Bioinformatics. 2012 May 24;13(1):111.

This work was supported by Polish Ministry of Science and Higher Education (grant NN301 190139).

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