criteria for classification as a protein scaffold

CRITERIA FOR CLASSIFICATION AS A PROTEIN SCAFFOLD SERIES

In the literature, the names are often used interchangeably, which indicates that the functions of the proteins in the four categories overlap significantly and they are often difficult to distinguished. by binding at least two signaling enzymes together and directing, coordinating and regulating their action ( Fig. 1). These proteins come under a variety of names, such as scaffold, adaptor, anchor and docking, but invariably function by ‘enforced proximity’, i.e. It is generally accepted that the primary mechanism is to promote the proximity of signaling enzymes by specific binding to a special class of regulatory proteins ]. Because of the multiplicity and broad substrate specificity of signaling enzymes, it is of immense importance to understand how the cell achieves efficiency and accuracy in signaling. post-synaptic density, disc large, zo-1 proteinĬells use a multitude of signaling proteins to alter cellular behavior in response to changes in their external and internal environment.non-catalytic region of tyrosine kinase adaptor protein.Fas-associated protein with death domain.dual-adapter for phosphotyrosine and 3-phosphoinositides.Thus, the field is in a state of continuous advance and expansion, which demands that the classification scheme be regularly updated and, if needed, revised. In addition, although not usually considered as scaffolds, several other proteins, such as regulatory proteins with catalytic activity, phosphatase targeting subunits, E3 ubiquitin ligases, ESCRT proteins in endosomal sorting and DNA damage sensors also function by bona fide scaffolding mechanisms. It will also be shown, however, that the categories partially overlap and often their names are used interchangeably in the literature. Here we discuss the categories of scaffolds, anchors, docking proteins and adaptors in some detail, and using many examples we demonstrate that they cover a wide range of functional modes that appear to segregate into three practical categories, simple proteins binding two partners together (adaptors), larger multidomain proteins targeting and regulating more proteins in complex ways (scaffold/anchoring proteins) and proteins specialized to initiate signaling cascades by localizing partners at the cell membrane (docking proteins).

By binding and bringing into proximity two or more signaling proteins, these proteins direct the flow of information in the cell by activating, coordinating and regulating signaling events in regulatory networks.

CRITERIA FOR CLASSIFICATION AS A PROTEIN SCAFFOLD SERIES

This preliminary evidence suggests that organic scaffolds with tight matches to the preferred loop scaffolds of proteins, implies the likelihood of the scaffold to be biologically relevant.In this series of four minireviews the field of scaffold proteins and proteins of similar molecular/cellular functions is overviewed. We found that peptidomimetic scaffolds with reported biological activities matched loop scaffold geometries and those peptidomimetic scaffolds with no reported biologically activities did not. This involved generation of a small dataset of scaffold-based peptidomimetics. We have used these 39 clusters that reflect the scaffold architecture of protein loops as biological descriptors. These protein loop scaffolds all have distinct shapes. We have found that 39 clusters reflect the scaffold architecture of 89% of the 23,331 loops in the dataset, with average intra-cluster and inter-cluster RMSD of 0.47 and 1.91, respectively.

Loops are an important molecular recognition motif of proteins. To decipher the scaffold architecture that is important for binding protein surfaces, we have analyzed the scaffold architecture of protein loops, which are defined in this context as continuous four residue segments of a protein chain that are not part of an α-helix or β-strand secondary structure. Since drug discovery is primarily focused on the discovery of compounds that bind to proteinaceous targets, we have been deciphering the scaffold shapes that are used for binding proteins as they reflect biologically relevant shapes. One role of the scaffold is to present its side-chains for molecular recognition, and biologically relevant scaffolds may present side-chains in biologically relevant geometries or shapes.

There is evidence suggesting that some scaffolds yield biologically active molecules more than others, these are termed privileged substructures. Medicinal chemists synthesize arrays of molecules by attaching functional groups to scaffolds.

Criteria for classification as a protein scaffold