Domain Interactions Mediate the Formation of Macromolecular Complexes

Interactions between domains can be divided in two main classes: intra-chain interactions, occurring only in multi-domain polypeptide chains, and inter-chain interactions, involving domains that reside in different polypeptide chains, as is the case for multi-subunit proteins or, more generically, for protein complexes. Since many protein-protein interactions are mediated by one or more inter-chain domain interactions, understanding how domain interfaces are formed and detailing their properties at the atomic level may shed some light on the inner workings of protein-protein interaction networks.

Inter-chain interactions show differences in their nature and, consequently, in their behavior: as we know, proteins spontaneously aggregate to form macromolecular complexes, either stably or transiently. Stable multi-protein complexes act as molecular machines that coordinate their action to carry out almost any biological process occurring in the cell. snRNP particles, responsible for directing splicing events in eukaryotes, the proteasome and nuclear pores, are good examples of molecular machines. Besides forming obligate complexes, the molecular components of which cannot exist separately (e.g., hemoglobin), proteins may associate to assemble transient complexes. Since the action of transient complexes is generally more confined in terms of space and time, the affinity of the bonds holding them together must be modulated so as to allow rapid assembly and disruption of the complex. Such capability to quickly re-model a protein complex is especially important in signaling pathways, where interaction events activate and direct the cell response to the possibly abrupt occurrence of external stimuli and swift changes in environmental conditions.

Permanent and non-obligate interfaces differ in size and polarity: permanent interfaces are usually large and hydrophobic, while non-obligate ones are smaller and more polar. Remarkably, intra-chain interfaces have physical and chemical properties that closely resemble those of inter-chain interfaces, usually intermediate between permanent and non-obligate interfaces (Park et al. 2001): this suggests that interactions within and between monomers are governed by the same underlying principles and, theoretically, no substantial difference should exist between an intra-chain domain interaction and an interaction between a pair of identical domains residing in different polypeptide chains. The phenomenon of domain swapping (one of the two domains forming an intra-chain interface is substituted by an identical domain belonging to another polypeptide chain) (Bennett et al. 1995), which is known to occur in the formation of some oligomeric proteins, is an example of such interchangeability among identical domains, regardless of the polypeptide chain they belong to. In fact, for domain swapping to occur, within monomer and between monomer interfaces must present similar interaction sites and must share similar characteristics (Jones et al. 2000).

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