Protein complex

A protein complex or multiprotein complex is a group of two or more associated

Through proximity, the speed and selectivity of binding interactions between enzymatic complex and substrates can be vastly improved, leading to higher cellular efficiency. Many of the techniques used to enter cells and isolate proteins are inherently disruptive to such large complexes, complicating the task of determining the components of a complex.

Examples of protein complexes include the

Protein complex formation can activate or inhibit one or more of the complex members and in this way, protein complex formation can be similar to phosphorylation. Individual proteins can participate in a variety of protein complexes. Different complexes perform different functions, and the same complex can perform multiple functions depending on various factors. Factors include:

• Cell compartment location
• Cell cycle stage
• Cell nutritional status^{[citation needed]}

Many protein complexes are well understood, particularly in the model organism Saccharomyces cerevisiae (yeast). For this relatively simple organism, the study of protein complexes is now genome wide and the elucidation of most of its protein complexes is ongoing.^{[citation needed]} In 2021, researchers used deep learning software RoseTTAFold along with AlphaFold to solve the structures of 712 eukaryote complexes. They compared 6000 yeast proteins to those from 2026 other fungi and 4325 other eukaryotes.^[4]

Types of protein complexes

Obligate vs non-obligate protein complex

If a protein can form a stable well-folded structure on its own (without any other associated protein) in vivo, then the complexes formed by such proteins are termed "non-obligate protein complexes". However, some proteins can't be found to create a stable well-folded structure alone, but can be found as a part of a protein complex which stabilizes the constituent proteins. Such protein complexes are called "obligate protein complexes".^[5]

Transient vs permanent/stable protein complex

Transient protein complexes form and break down transiently in vivo, whereas permanent complexes have a relatively long half-life. Typically, the obligate interactions (protein–protein interactions in an obligate complex) are permanent, whereas non-obligate interactions have been found to be either permanent or transient.^[5] Note that there is no clear distinction between obligate and non-obligate interaction, rather there exist a continuum between them which depends on various conditions e.g. pH, protein concentration etc.^[6] However, there are important distinctions between the properties of transient and permanent/stable interactions: stable interactions are highly conserved but transient interactions are far less conserved, interacting proteins on the two sides of a stable interaction have more tendency of being co-expressed than those of a transient interaction (in fact, co-expression probability between two transiently interacting proteins is not higher than two random proteins), and transient interactions are much less co-localized than stable interactions.^[7] Though, transient by nature, transient interactions are very important for cell biology: the human interactome is enriched in such interactions, these interactions are the dominating players of gene regulation and signal transduction, and proteins with intrinsically disordered regions (IDR: regions in protein that show dynamic inter-converting structures in the native state) are found to be enriched in transient regulatory and signaling interactions.^[5]

Fuzzy complex

Fuzzy protein complexes have more than one structural form or dynamic structural disorder in the bound state.^[8] This means that proteins may not fold completely in either transient or permanent complexes. Consequently, specific complexes can have ambiguous interactions, which vary according to the environmental signals. Hence different ensemble of structures result in different (even opposite) biological functions.^[9] Post-translational modifications, protein interactions or alternative splicing modulate the conformational ensembles of fuzzy complexes, to fine-tune affinity or specificity of interactions. These mechanisms are often used for regulation within the eukaryotic transcription machinery.^[10]

Essential proteins in protein complexes

Although some early studies

In humans, genes whose protein products belong to the same complex are more likely to result in the same disease phenotype.[17]^[18][19]

Homomultimeric and heteromultimeric proteins

The subunits of a multimeric protein may be identical as in a homomultimeric (homooligomeric) protein or different as in a heteromultimeric protein. Many soluble and membrane proteins form homomultimeric complexes in a cell, majority of proteins in the Protein Data Bank are homomultimeric.^[20] Homooligomers are responsible for the diversity and specificity of many pathways, may mediate and regulate gene expression, activity of enzymes, ion channels, receptors, and cell adhesion processes.

The

When multiple copies of a polypeptide encoded by a gene form a complex, this protein structure is referred to as a multimer. When a multimer is formed from polypeptides produced by two different mutant alleles of a particular gene, the mixed multimer may exhibit greater functional activity than the unmixed multimers formed by each of the mutants alone. In such a case, the phenomenon is referred to as intragenic complementation (also called inter-allelic complementation). Intragenic complementation has been demonstrated in many different genes in a variety of organisms including the fungi Neurospora crassa, Saccharomyces cerevisiae and Schizosaccharomyces pombe; the bacterium Salmonella typhimurium; the virus bacteriophage T4,^[21] an RNA virus^[22] and humans.^[23] In such studies, numerous mutations defective in the same gene were often isolated and mapped in a linear order on the basis of recombination frequencies to form a genetic map of the gene. Separately, the mutants were tested in pairwise combinations to measure complementation. An analysis of the results from such studies led to the conclusion that intragenic complementation, in general, arises from the interaction of differently defective polypeptide monomers to form a multimer.^[24] Genes that encode multimer-forming polypeptides appear to be common. One interpretation of the data is that polypeptide monomers are often aligned in the multimer in such a way that mutant polypeptides defective at nearby sites in the genetic map tend to form a mixed multimer that functions poorly, whereas mutant polypeptides defective at distant sites tend to form a mixed multimer that functions more effectively. The intermolecular forces likely responsible for self-recognition and multimer formation were discussed by Jehle.^[25]

Structure determination

The

The structure of proteins play a role in how the multiprotein complex assembles. The interfaces between proteins can be used to predict assembly pathways.[28] The intrinsic flexibility of proteins also plays a role: more flexible proteins allow for a greater surface area available for interaction.^[30]

While assembly is a different process from disassembly, the two are reversible in both homomeric and heteromeric complexes. Thus, the overall process can be referred to as (dis)assembly.

Evolutionary significance of multiprotein complex assembly

In homomultimeric complexes, the homomeric proteins assemble in a way that mimics evolution. That is, an intermediate in the assembly process is present in the complex's evolutionary history.^[31] The opposite phenomenon is observed in heteromultimeric complexes, where gene fusion occurs in a manner that preserves the original assembly pathway.^[28]

See also

• Heterotetramer
• Biomolecular complex
• Protein subunit

References