Proteins are molecular machines that perform cellular functions, built from smaller units called protein domains, each with a distinct function. Among these, the “sushi domain” is a compact structural unit that plays a wide range of roles in biological processes, particularly within the immune system.
Decoding the Sushi Domain
A sushi domain is a compact protein module, composed of 60 to 70 amino acids. Its structural stability comes from two disulfide bonds formed by four cysteine residues. These bonds help fold the domain into a beta-sandwich arrangement, featuring one face with three hydrogen-bonded beta-strands and another with two separate beta-strands. The name “sushi domain” refers to the visual resemblance of its structure, when drawn with loops created by the disulfide bonds, to a piece of nigiri sushi.
This domain is also known as the Complement Control Protein (CCP) module or Short Consensus Repeat (SCR). These names highlight its prevalence in proteins that regulate the complement system, a part of the immune response. A highly conserved tryptophan, along with conserved glycine, proline, and hydrophobic residues, defines its characteristic sequence. This distinct structural signature allows it to participate in various molecular interactions within diverse biological contexts.
Ubiquitous Presence Across Life
Sushi domains are broadly distributed across many organisms, reflecting their ancient evolutionary origins and conserved importance. They are found in invertebrates, such as Caenorhabditis elegans and Drosophila melanogaster, as well as in vertebrates like humans. This widespread presence suggests a fundamental role in basic biological mechanisms that have been maintained throughout evolution.
These domains are commonly found in proteins that function in the extracellular environment or are embedded in cell membranes. Many proteins of the complement system, a part of innate immunity, contain multiple sushi domains. They are also present in cell adhesion molecules, which help cells stick together and interact with their surroundings, as well as in various receptors and extracellular matrix proteins. This broad distribution reflects their versatility as modular building blocks for diverse biological machinery.
Diverse Roles in Biological Processes
Sushi domains are integral to various biological processes, with a significant impact on immune system function. They regulate the complement cascade, a complex part of the innate immune response that helps identify and clear pathogens. Proteins containing sushi domains, such as decay-accelerating factor (DAF) and complement receptor 1 (CR1), help control the activation of complement factors like C3b and C4b, preventing uncontrolled immune responses that could harm healthy cells. Some sushi domain-containing proteins, like SUSD4, can augment the alternative pathway of complement activation by interacting with C3b.
Sushi domains also contribute to cell-cell recognition and adhesion. Proteins like P-selectin, which contains sushi domains, mediate the interaction of activated endothelial cells or platelets with white blood cells, a process central to inflammation and immune cell recruitment. These domains are involved in signal transduction, allowing cells to receive and respond to external cues. For example, G protein-coupled receptors, like GABAB receptors, utilize sushi domains for proper protein interactions and cellular localization. This highlights their ability to act as molecular interfaces, facilitating communication and coordination between cells.
Implications for Health and Disease
The widespread involvement of sushi domains in fundamental biological processes means that their dysfunction can have significant consequences for human health. Mutations or dysregulation in proteins containing these domains are linked to various conditions. For example, deletions in the SUSD4 gene, which contains four sushi domains, have been identified in patients with autism or Fryns syndrome, conditions characterized by abnormal neurological development. Mutations in SRPX2, another sushi domain-containing protein, are associated with epilepsy and speech dysfunction.
Disruptions in proteins with sushi domains can also affect immune regulation, potentially leading to autoimmune diseases or increased susceptibility to infections. For instance, specific complement regulatory proteins containing sushi domains, if faulty, could lead to uncontrolled complement activation and tissue damage. The potential of sushi domain-containing proteins like SUSD3 and SUSD4 to act as biomarkers or therapeutic targets is being explored in conditions such as breast cancer and bladder cancer. Understanding these domains offers avenues for developing new diagnostic tools and therapeutic strategies to address a range of human diseases.