A protein superfamily is the largest grouping ( clade ) of proteins for which common ancestry can be inferred (see homology ). Usually this common ancestry is inferred from structural alignment and mechanistic similarity, even if no sequence similarity is evident. Sequence homology can then be deduced even if not apparent (due to low sequence similarity). Superfamilies typically contain several protein families which show sequence similarity within each family. The term protein clan is commonly used for protease and glycosyl hydrolases superfamilies based on the MEROPS and CAZy classification systems.
31-409: The tumor necrosis factor receptor superfamily ( TNFRSF ) is a protein superfamily of cytokine receptors characterized by the ability to bind tumor necrosis factors (TNFs) via an extracellular cysteine -rich domain. With the exception of nerve growth factor (NGF), all TNFs are homologous to the archetypal TNF-alpha . In their active form, the majority of TNF receptors form trimeric complexes in
62-446: A lower Gibbs free energy (a combination of enthalpy and entropy ) than the unfolded conformation. A protein will tend towards low-energy conformations, which will determine the protein's fold in the cellular environment. Because many similar conformations will have similar energies, protein structures are dynamic , fluctuating between these similar structures. Globular proteins have a core of hydrophobic amino acid residues and
93-609: A number of ways. The interactions and bonds of side chains within a particular protein determine its tertiary structure. The protein tertiary structure is defined by its atomic coordinates. These coordinates may refer either to a protein domain or to the entire tertiary structure. A number of these structures may bind to each other, forming a quaternary structure . The science of the tertiary structure of proteins has progressed from one of hypothesis to one of detailed definition. Although Emil Fischer had suggested proteins were made of polypeptide chains and amino acid side chains, it
124-411: A protein will reach its native state, given its chemical kinetics , before it is translated . Protein chaperones within the cytoplasm of a cell assist a newly synthesised polypeptide to attain its native state. Some chaperone proteins are highly specific in their function, for example, protein disulfide isomerase ; others are general in their function and may assist most globular proteins, for example,
155-533: A superfamily is commonly conserved, although substrate specificity may be significantly different. Catalytic residues also tend to occur in the same order in the protein sequence. For the families within the PA clan of proteases, although there has been divergent evolution of the catalytic triad residues used to perform catalysis, all members use a similar mechanism to perform covalent, nucleophilic catalysis on proteins, peptides or amino acids. However, mechanism alone
186-433: A surface region of water -exposed, charged, hydrophilic residues. This arrangement may stabilize interactions within the tertiary structure. For example, in secreted proteins, which are not bathed in cytoplasm , disulfide bonds between cysteine residues help to maintain the tertiary structure. There is a commonality of stable tertiary structures seen in proteins of diverse function and diverse evolution . For example,
217-451: A wide variety of tissues in mammals, especially in leukocytes . The term death receptor refers to those members of the TNF receptor superfamily that contain a death domain , such as TNFR1, Fas receptor , DR4 and DR5 . They were named after the fact that they seemed to play an important role in apoptosis (programmed cell death), although they are now known to play other roles as well. In
248-455: Is conserved through the superfamily, not even those in the catalytic triad . Conversely, the individual families that make up a superfamily are defined on the basis of their sequence alignment, for example the C04 protease family within the PA clan. Nevertheless, sequence similarity is the most commonly used form of evidence to infer relatedness, since the number of known sequences vastly outnumbers
279-424: Is currently possible. They are therefore amongst the most ancient evolutionary events currently studied. Some superfamilies have members present in all kingdoms of life , indicating that the last common ancestor of that superfamily was in the last universal common ancestor of all life (LUCA). Superfamily members may be in different species, with the ancestral protein being the form of the protein that existed in
310-443: Is done by causing the disease in laboratory animals, for example, by administering a toxin , such as MPTP to cause Parkinson's disease, or through genetic manipulation . Protein structure prediction is a new way to create disease models, which may avoid the use of animals. Matching patterns in tertiary structure of a given protein to huge number of known protein tertiary structures and retrieve most similar ones in ranked order
341-554: Is limited to smaller proteins. However, it can provide information about conformational changes of a protein in solution. Cryogenic electron microscopy (cryo-EM) can give information about both a protein's tertiary and quaternary structure. It is particularly well-suited to large proteins and symmetrical complexes of protein subunits . Dual polarisation interferometry provides complementary information about surface captured proteins. It assists in determining structure and conformation changes over time. The Folding@home project at
SECTION 10
#1732797828255372-447: Is no minimum level of sequence similarity guaranteed to produce identical structures. Over long periods of evolution, related proteins may show no detectable sequence similarity to one another. Sequences with many insertions and deletions can also sometimes be difficult to align and so identify the homologous sequence regions. In the PA clan of proteases , for example, not a single residue
403-445: Is not sufficient to infer relatedness. Some catalytic mechanisms have been convergently evolved multiple times independently, and so form separate superfamilies, and in some superfamilies display a range of different (though often chemically similar) mechanisms. Protein superfamilies represent the current limits of our ability to identify common ancestry. They are the largest evolutionary grouping based on direct evidence that
434-579: Is typically more conserved than DNA sequence (due to the degenerate genetic code ), so it is a more sensitive detection method. Since some of the amino acids have similar properties (e.g., charge, hydrophobicity, size), conservative mutations that interchange them are often neutral to function. The most conserved sequence regions of a protein often correspond to functionally important regions like catalytic sites and binding sites, since these regions are less tolerant to sequence changes. Using sequence similarity to infer homology has several limitations. There
465-533: Is very rare to find “consistently isolated superfamilies”. When domains do combine, the N- to C-terminal domain order (the "domain architecture") is typically well conserved. Additionally, the number of domain combinations seen in nature is small compared to the number of possibilities, suggesting that selection acts on all combinations. Several biological databases document protein superfamilies and protein folds, for example: Similarly there are algorithms that search
496-459: The PDB for proteins with structural homology to a target structure, for example: Protein tertiary structure Protein tertiary structure is the three-dimensional shape of a protein . The tertiary structure will have a single polypeptide chain "backbone" with one or more protein secondary structures , the protein domains . Amino acid side chains and the backbone may interact and bond in
527-490: The TIM barrel , named for the enzyme triosephosphateisomerase , is a common tertiary structure as is the highly stable, dimeric , coiled coil structure. Hence, proteins may be classified by the structures they hold. Databases of proteins which use such a classification include SCOP and CATH . Folding kinetics may trap a protein in a high- energy conformation, i.e. a high-energy intermediate conformation blocks access to
558-762: The University of Pennsylvania is a distributed computing research effort which uses approximately 5 petaFLOPS (≈10 x86 petaFLOPS) of available computing. It aims to find an algorithm which will consistently predict protein tertiary and quaternary structures given the protein's amino acid sequence and its cellular conditions. A list of software for protein tertiary structure prediction can be found at List of protein structure prediction software . Protein aggregation diseases such as Alzheimer's disease and Huntington's disease and prion diseases such as bovine spongiform encephalopathy can be better understood by constructing (and reconstructing) disease models . This
589-469: The prokaryotic GroEL / GroES system of proteins and the homologous eukaryotic heat shock proteins (the Hsp60/Hsp10 system). Prediction of protein tertiary structure relies on knowing the protein's primary structure and comparing the possible predicted tertiary structure with known tertiary structures in protein data banks . This only takes into account the cytoplasmic environment present at
620-438: The ancestral species ( orthology ). Conversely, the proteins may be in the same species, but evolved from a single protein whose gene was duplicated in the genome ( paralogy ). A majority of proteins contain multiple domains. Between 66-80% of eukaryotic proteins have multiple domains while about 40-60% of prokaryotic proteins have multiple domains. Over time, many of the superfamilies of domains have mixed together. In fact, it
651-433: The formation of weak bonds between amino acid side chains - Determined by the folding of the polypeptide chain on itself (nonpolar residues are located inside the protein, while polar residues are mainly located outside) - Envelopment of the protein brings the protein closer and relates a-to located in distant regions of the sequence - Acquisition of the tertiary structure leads to the formation of pockets and sites suitable for
SECTION 20
#1732797828255682-426: The host cell membrane . Some tertiary protein structures may exist in long-lived states that are not the expected most stable state. For example, many serpins (serine protease inhibitors) show this metastability . They undergo a conformational change when a loop of the protein is cut by a protease . It is commonly assumed that the native state of a protein is also the most thermodynamically stable and that
713-462: The lowest-energy conformation. The high-energy conformation may contribute to the function of the protein. For example, the influenza hemagglutinin protein is a single polypeptide chain which when activated, is proteolytically cleaved to form two polypeptide chains. The two chains are held in a high-energy conformation. When the local pH drops, the protein undergoes an energetically favorable conformational rearrangement that enables it to penetrate
744-402: The most evolutionarily divergent members. Historically, the similarity of different amino acid sequences has been the most common method of inferring homology . Sequence similarity is considered a good predictor of relatedness, since similar sequences are more likely the result of gene duplication and divergent evolution , rather than the result of convergent evolution . Amino acid sequence
775-597: The number of known tertiary structures . In the absence of structural information, sequence similarity constrains the limits of which proteins can be assigned to a superfamily. Structure is much more evolutionarily conserved than sequence, such that proteins with highly similar structures can have entirely different sequences. Over very long evolutionary timescales, very few residues show detectable amino acid sequence conservation, however secondary structural elements and tertiary structural motifs are highly conserved. Some protein dynamics and conformational changes of
806-566: The plasma membrane. Accordingly, most TNF receptors contain transmembrane domains (TMDs), although some can be cleaved into soluble forms (e.g. TNFR1 ), and some lack a TMD entirely (e.g. DcR3 ). In addition, most TNF receptors require specific adaptor protein such as TRADD , TRAF , RIP and FADD for downstream signalling. TNF receptors are primarily involved in apoptosis and inflammation , but they can also take part in other signal transduction pathways, such as proliferation , survival, and differentiation . TNF receptors are expressed in
837-563: The protein structure may also be conserved, as is seen in the serpin superfamily . Consequently, protein tertiary structure can be used to detect homology between proteins even when no evidence of relatedness remains in their sequences. Structural alignment programs, such as DALI , use the 3D structure of a protein of interest to find proteins with similar folds. However, on rare occasions, related proteins may evolve to be structurally dissimilar and relatedness can only be inferred by other methods. The catalytic mechanism of enzymes within
868-600: The recognition and the binding of specific molecules (biospecificity). The knowledge of the tertiary structure of soluble globular proteins is more advanced than that of membrane proteins because the former are easier to study with available technology. X-ray crystallography is the most common tool used to determine protein structure . It provides high resolution of the structure but it does not give information about protein's conformational flexibility . Protein NMR gives comparatively lower resolution of protein structure. It
899-479: The strict sense, the term TNF receptor is often used to refer to the archetypal members of the superfamily, namely TNFR1 and TNFR2 , which recognize TNF-alpha. There are 27 family members, numerically classified as TNFRSF#, where # denotes the member number, sometimes followed a letter. Protein superfamily Superfamilies of proteins are identified using a number of methods. Closely related members can be identified by different methods to those needed to group
930-466: The time of protein synthesis to the extent that a similar cytoplasmic environment may also have influenced the structure of the proteins recorded in the protein data bank. The structure of a protein, such as an enzyme , may change upon binding of its natural ligands, for example a cofactor . In this case, the structure of the protein bound to the ligand is known as holo structure, while the unbound protein has an apo structure. Structure stabilized by
961-577: Was Dorothy Maud Wrinch who incorporated geometry into the prediction of protein structures . Wrinch demonstrated this with the Cyclol model , the first prediction of the structure of a globular protein . Contemporary methods are able to determine, without prediction, tertiary structures to within 5 Å (0.5 nm) for small proteins (<120 residues) and, under favorable conditions, confident secondary structure predictions. A protein folded into its native state or native conformation typically has