Structural Biochemistry, Serpins

Introduction

Serpins are a very large class of proteins that have a wide range of functions, with the most important being inhibition of proteases. The name "serpin" stands for Serine Protease Inhibitors since they replicate the 3D structure of their respective serine protease and block its structure and pathway. Ultimately, serpines hinder the linkage of amino acids in a polypeptide chain which essentially make up the protein and force it to be inactive.
There are over 1000 serpins known today in humans, plants, bacteria, fungi, and even viruses. Many serpins play significant roles in protein catabolism and the first ones to be studied were antitrypsin and antithrombin, which are types of human plasma proteins. Researchers found that these proteins mediated blood inflammation and coagulation respectively and were crucial in human development. A mishap with either of these two Serpins causes diseases such as thrombosis and emphysema.

Example of serpin Structure (Image: Jawahar Swaminathan and MSD staff at the European Bioinformatics Institute, Public domain)

Serpin Structure

Analyzing the structure of serpins has helped figure their function and role in the biological world. Although each serpin slightly varies in conformation to make it distinct from the others, most serpins have a similar ordered structure.
The first serpins that were studied, antitrypsin and antithrombin, showed that all serpins have a distinct fold which allows them to fit inside other proteins and inhibit their functions. Serpins are composed of three β-sheets (referred to as A, B and C), about nine α-helices, and an open region (known as the center loop) which is the site of reaction. The center loop, known as RCL, is the reaction site which initiates inhibition processes and does not always appear on the same area for all serpines. The difference of where the RCL is situated distinguishes each serpine from the next.

Researchers have found around 36 serpin genes in humans which are classified depending on their structure. Naming of the serpin includes the name of the gene, following by the word "SERPIN", followed by a letter that corresponds to the class of serpin and a number for the specific gene in the class.

Serpin Function

The main function of serpins is to inhibit proteases, especially serine protease which gives serpines their name.
Some serpins also perform other functions which are noninhibitory. For example, Ovalbumin (found in egg whites) is a serpine which can store nutrients for the egg, thyroxine-hinding globulin is another serpine which transports hormones to various parts of the body, and Maspin is a serpine which controls gene expression of certain tumors.

Mechanism of Protease Inhibition (Image: Jcwhizz, Public domain)

Serpins with inhibitory roles hinder functions of other proteins, such as protesaes. The way in which they block activity is by attaching to the other protein in a specific structural orientation to stop them from fully functioning. After they have attached to a target, they oversee structural conformations in their target protein which are usually permanent so that the protein cannot perform any other functions. Although the serpin is generally efficient in performing its job, certain mishaps can lead to mutations or protein misfolding, which would inactivate chains of polymers and confirm long protein chains to be useless.

Serpin Mutations and Diseases

The structure and function of a serpin are easily changed when mutations occur. If protein building is altered, such as a change in the amino acid sequence or a distinction in folding, the identity of the serpin will change. Even a small change in structure will affect the entire function of the serpin and may deem it useless and/or even harmful. Changes in serpin structure leading to genetic disorders or abnormalities are called Serpinopathies. As mentioned earlier, diseases such as emphysema, thrombosis, angiodema, dementia, etc. can result from Serpinopathies.

Two main defects can occur in the body when a Serpin undergoes a mutation. In the first defect, the inactive serpin fails to perform its blocking job and causes the protease to fuel many defects in the body. An example of this defect is emphysema, in which alpha 1-antitrypsin does not perform its duties and the elastase is destructive and incorrectly eliminates useful tissues in the lungs. The second type of defect is when serpins often clump together into bunches and cause harm to the cell by raising the toxicity levels. An example of this defect is clumping of nerve cells in the brain, which results to familial dementia. If many mutations occur, the usual inhibiting functions will not be carried out and the cell can suffer.

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References

• ↑

1. Goodsell, David (2004). Serpins'. "Protein Data Bank"
2. Gettins PG. (2002). Serpin structure, mechanism, and function'. "PubMed"
3. Gooptu B, Lomas DA. (2009). Conformational pathology of the serpins: themes, variations, and therapeutic strategies.'. "PubMed"

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