Domain SH2 Characteristics, Structure and Functions

2018
Jonah Lester

The SH2 domain (Src Homology 2) is a highly conserved protein domain in evolution and present in more than 100 different proteins, the most prominent being the src oncoprotein, involved in the signal transduction process within the cell.

The function of the domain is binding to phosphorylated tyrosine sequences on target proteins; This union triggers a series of signals that regulate the expression of genes. This domain has also been found in the enzyme tyrosine phosphatase.

SH2 domains are generally found together with other domains that have been associated with signal transduction pathways. One of the most common interactions is the connection with the SH2 and SH3 domain, which seems to be involved in regulating the interaction with sequences rich in proline..

Proteins can contain a single SH2 domain or more than one, such as the GAP protein and the p85 subunit of phosphoinositol 3-kinases..

The SH2 domain has been widely studied by the pharmaceutical industry in order to generate drugs to combat diseases such as cancer, allergies, autoimmune diseases, asthma, AIDS, osteoporosis, among others..

Article index

  • 1 Features
  • 2 Structure
  • 3 Functions
  • 4 Evolution
  • 5 Clinical implications
    • 5.1 X-linked lymphoproliferative
    • 5.2 X-linked agammaglobulinemia
    • 5.3 Noonan syndrome
  • 6 References

Characteristics

The SH2 domain consists of about 100 amino acids connected to catalytic domains. The most obvious example are tyrosine kinase enzymes, which are responsible for catalyzing the transfer of a phosphate group from ATP to tyrosine amino acid residues..

Additionally, SH2 domains have been reported in non-catalytic domains such as crk, grb2 / sem5, and nck..

SH2 domains are present in higher eukaryotes and it has been suggested that they also appear in yeast. With regard to bacteria, in Escherichia coli a module that reminds SH2 domains has been reported.

The src protein is the first tyrosine kinase discovered, which when mutated is probably involved in the regulation of kinase activity and also in promoting the interactions of these proteins with other components within the cell.

After the discovery of the domains in the scr protein, the SH2 domain was identified in a significant number of highly varied proteins, including protein tyrosine kinases and transcription factors..

Structure

The structure of the SH2 domain has been revealed by the use of techniques such as X-ray diffraction, crystallography and NMR (nuclear magnetic resonance), finding common patterns in the secondary structure of the SH2 domains studied..

The SH2 domain has five highly conserved motifs. A generic domain is composed of core β sheets with small adjacent portions of antiparallel β sheets, flanked by two α helixes..

Amino acid residues on one side of the leaf and in the N-terminal αA region are involved in coordinating the binding of peptides. However, the rest of the characteristics of the proteins is quite variable among the studied domains..

In the terminal carbon portion, an isoleucine residue is found in the third position and forms a hydrophobic pocket on the surface of the SH2 domain..

An important characteristic is the existence of two regions, each with a particular function. The area between the first α helix and the β sheet is the phosphotyrosine recognition site.

Likewise, the region between the β sheet and the α helix of the terminal carbon form a region responsible for interacting with the terminal carbon residues of phosphotyrosine.

Features

The function of the SH2 domain is the recognition of the phosphorylation state in the tyrosine amino acid residues. This phenomenon is crucial in signal transduction, when a molecule located outside the cell is recognized by a receptor on the membrane and processed inside the cell..

Signal transduction is an extremely important regulatory event, in which the cell responds to changes in its extracellular environment. This process occurs thanks to the transduction of external signals contained in certain molecular messengers through its membrane..

Tyrosine phosphorylation leads to the sequential activation of protein-protein interactions, which results in a change in gene expression or an alteration in cellular response.

Proteins containing SH2 domains are involved in regulatory pathways related to essential cellular processes, such as cytoskeletal rearrangement, homeostasis, immune responses, and development..

Evolution

The presence of the SH2 domain has been reported in the primitive unicellular organism Monosiga brevicollis. This domain is thought to have evolved as an invariable signaling unit with the appearance of tyrosine phosphorylation..

It is speculated that the ancestral arrangement of the domain served to direct the kinases to their substrates. Thus, with the increase in complexity in organisms, the SH2 domains acquired new functions in the course of evolution, such as the allosteric regulation of the catalytic domain of kinases..

Clinical implications

X-linked lymphoproliferative

Some mutated SH2 domains have been identified as causing disease. Mutations in the SH2 domain in SAP cause X-linked lymphoproliferative disease, which causes a high increase in sensitivity to certain viruses and thus uncontrolled proliferation of B cells..

Proliferation occurs because the mutation of the SH2 domains causes failures in the signaling pathways between B and T cells, leading to viral infections and uncontrolled B cell growth. This disease has a high mortality rate.

X-linked agammaglobulinemia

Similarly, strut mutations in the SH2 domain of Bruton's protein kinase are responsible for a condition called agammaglobulinemia..

This condition is linked to the X chromosome, is characterized by a lack of B cells and a marked decrease in immunoglobulin concentrations.

Noonan syndrome

Finally, mutations in the N-terminal region of the SH2 domain in the protein tyrosine phosphatase 2 are the cause of Noonan syndrome..

This pathology is mainly characterized by heart disease, short stature due to slower growth rate, and facial and skeletal abnormalities. In addition, the condition may present mental and psychomotor retardation in a quarter of the cases studied..

References

  1. Berg, J. M., Stryer, L., & Tymoczko, J. L. (2007). Biochemistry. I reversed.
  2. Filippakopoulos, P., Müller, S., & Knapp, S. (2009). SH2 domains: modulators of nonreceptor tyrosine kinase activity. Current Opinion in Structural Biology, 19(6), 643-649.
  3. Kurochkina, N. (Ed.). (2015). Sh Domains: Structure, Mechanisms and Applications. Springer.
  4. Sawyer, T. K. (1998). Src homology ‐ 2 domains: Structure, mechanisms, and drug discovery. Peptide Science, 47(3), 243-261.
  5. Schlessinger, J. (1994). SH2 / SH3 signaling proteins. Current opinion in genetics & development, 4(1), 25-30.

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