The folding and evolution of multidomain proteins

Abstract

Analyses of genomes show that more than 70% of eukaryotic proteins are composed of multiple domains. However, most studies of protein folding focus on individual domains and do not consider how interactions between domains might affect folding. Here, we address this by analysing the three-dimensional structures of multidomain proteins that have been characterized experimentally and observe that where the interface is small and loosely packed, or unstructured, the folding of the domains is independent. Furthermore, recent studies indicate that multidomain proteins have evolved mechanisms to minimize the problems of interdomain misfolding.

Ubiquitin not only serves as a tag but also assists degradation by inducing protein unfolding

“…In a similar manner, we conjugated this chain topology to an additional seven of the nine surface-exposed Lys residues that were shown not to be ubiquitinated in vivo (3,11,18,29,62, 70, and 161). We chose these residues on the basis of the propensity of ubiquitination to occur mostly in loop regions and to a lesser extent on helices (31,32).…”

“…When proteins were covalently linked in vitro (10), their thermal stability was significantly altered. Studies of multidomain proteins show that the folding characteristics of their isolated constituent domains can be dramatically changed when they are connected to a neighboring domain (11)(12)(13). Furthermore, several studies speculated that ubiquitination may alter various biophysical properties, such as protein stability (14,15), conformational dynamics (16), solubility, and refolding competence (17).…”

Cooperativity, connectivity, and folding pathways of multidomain proteins

“…More than 70% of eukaryotic proteins, however, are composed of multiple domains, and hence we should ask whether the principles of folding found in single domains of proteins also apply to connected multidomain proteins as well (11). Anticorrelation between the contact order and the folding rate has been observed in multidomain proteins (12), and the structure-based simulations on multidomain proteins such as the ankyrin family (13)(14)(15) and CV-N (16) have provided consistent results with experiments.…”

“…For example, when isolated individual domains that can fold and unfold independently of other domains are connected to a multidomain protein, domains would still behave independently or behave cooperatively through the domain-domain interactions. Although both cooperative folding and independent folding of domains have been observed (11), whether topology determines the cooperativity has not yet been clarified. To shed light on this problem, we here analyze the folding of the example proteins human ␥D-crystallin (17)(18)(19)(20)(21)(22), protein S (23,24), and a tandem array of the R16 and R17 domains of spectrin (25)(26)(27)(28) by using a simple structure-based model and show that the model indeed captures the essential features of the folding of these multidomain proteins.…”

BioSilicoSystems - A Multipronged Approach Towards Analysis and Representation of Biological Data (PhD Thesis)

“…Often it may be that even in protein that share little sequence similarity the structural similarities are present, as the structure conservation is stronger than the sequence conservation. Therefore in order to identify the distant relationship between proteins structure based classification is more effective than are sequence based methods and approaches (Han et al 2007). Here a new approach to align biological pathways is proposed which is based on the rudimentary biochemical knowledge.…”