#proteinstructure

Spinning Spider Proteins

Tarantula spider proteins have helped scientists to understand for the first time how genetic changes in heart muscle cause different forms of cardiomyopathy, one of the most common causes of heart failure and sudden death in otherwise healthy young people. At first glance, hairy eight-legged spiders appear to have little in common with people. But some of the proteins that make up a spider’s muscles are similar to those in our own bodies, including our hearts. Researchers chose to study spider proteins because it allowed them to explore their 3D structure and how they interact with their neighbours in much greater detail than is possible with human models. They focused on the muscle protein myosin. Here, different parts of myosin are shown in different colours. Coloured dots indicate mutations that block it from interacting with other proteins, which in turn stops the heart from relaxing, and can cause cardiomyopathy.

Read more on this story here.

Written by Deborah Oakley

Image/video from work by Lorenzo Alamo, James S. Ware Christine E. Seidman and Raúl Padrón

MRC London Institute of Medical Sciences, Imperial College London; Venezuelan Institute for Scientific Research; Department of Genetics, Harvard Medical School, Boston, USA

Image originally published under a Creative Commons Licence (BY 4.0)

Published in eLife, June 2017

Proteins are essential to life, playing a crucial role in a wide range of biological processes. As one of the most extensively studied biomolecules in both biology and chemistry, proteins are vital to understanding how life functions. A comprehensive grasp of protein structure is necessary to fully appreciate their diverse functions, interactions, and roles within living organisms. This guide provides an in-depth exploration of protein structure, classification, and the various levels of their organization.  

What is the Structure of Protein?  

Protein structure refers to the three-dimensional arrangement of amino acid chains within a protein. Proteins are made up of long chains of amino acids connected by peptide bonds, which fold into specific shapes influenced by the sequence of amino acids and the interactions between them. The unique structure of each protein determines its function, whether it’s acting as an enzyme to catalyze reactions, providing structural support, or facilitating cellular communication.  

Proteins are constructed from 20 different amino acids, each with distinctive side chains that affect the protein’s overall shape and properties. The sequence of amino acids in a protein is encoded by genes, and even a minor change in this sequence can significantly impact the protein’s function.  

Protein structure is organized into four distinct levels:  

Primary Structure: This is the linear sequence of amino acids in a polypeptide chain, representing the most basic level of protein structure, as determined by the genetic code.  

Secondary Structure: This stage refers to the specific folding of the polypeptide chain into configurations such as alpha helices and beta sheets, which are maintained by hydrogen bonds.  

Tertiary Structure: This refers to the overall three-dimensional folding of the entire polypeptide chain, resulting from various interactions between side chains.  

Quaternary Structure: This structural level isn’t present in all proteins. It refers to the combination of multiple polypeptide chains forming a functional protein complex.  

Classification of Proteins  

Proteins can be classified based on their structure and function. The two primary categories are fibrous proteins and globular proteins.  

Fibrous Proteins  

Fibrous proteins are elongated, thread-like structures that are insoluble in water. They mainly provide structural support and are found in tissues such as tendons, ligaments, and skin. Their extended, linear shape allows them to form strong fibers, making them ideal for mechanical support.  

Examples of fibrous proteins include:  

Collagen: The most abundant protein in mammals, collagen is a key component of connective tissues, providing tensile strength to skin, bones, and tendons.  

Keratin: Present in hair, nails, and the outer layer of skin, keratin is a durable, protective protein that provides structural support.  

Fibrous proteins have a simple, repetitive sequence that enables the formation of stable, strong structures. They primarily serve structural roles rather than functional ones and typically do not undergo significant conformational changes.  

Globular Proteins  

Globular proteins are compact, spherical proteins that are soluble in water. Unlike fibrous proteins, they play a role in a wide variety of biological functions, including catalysis, transport, and regulation. Their complex three-dimensional shapes are crucial to their functions.  

Examples of globular proteins include:  

Hemoglobin: A protein in red blood cells responsible for transporting oxygen from the lungs to the rest of the body.  

Enzymes: These are proteins that function as biological catalysts, accelerating chemical reactions within the body.  

Globular proteins have dynamic structures that allow them to interact with various molecules. They are generally more complex than fibrous proteins and can undergo significant conformational changes during their function.  

Levels of Protein Structure  

Primary Structure of Protein  

A protein’s primary structure is its unique sequence of amino acids, determined by the organism’s DNA. This sequence is critical for the protein’s final shape and function, dictating how the protein will fold into its secondary, tertiary, and quaternary structures.  

Each amino acid in the sequence is connected by a peptide bond, creating a polypeptide chain. Even a single alteration in this sequence, such as a mutation, can result in a non-functional protein or cause diseases.  

Secondary Structure of Protein  

The secondary structure of a protein refers to the local folding of the polypeptide chain into specific patterns, such as alpha helices and beta sheets. These structures are maintained by hydrogen bonds that form between the backbone atoms of the amino acids.  

Alpha Helices: Coiled structures resembling a spiral staircase, with amino acid side chains extending outward. Alpha helices are common in many proteins and contribute to their stability and flexibility.  

Beta Sheets: Sheet-like structures formed by linking two or more strands of a polypeptide chain through hydrogen bonds. Beta sheets can be parallel or antiparallel, depending on the direction of the strands.  

These secondary structures are essential for the protein’s overall folding and stability, as they bring distant parts of the polypeptide chain closer together.  

Tertiary Structure of Protein  

The tertiary structure is the overall three-dimensional shape of a protein, formed by the folding of its secondary structures. This structural level is supported by various interactions, including hydrogen bonds, ionic bonds, hydrophobic interactions, and disulfide bridges.  

The tertiary structure is vital for the protein’s function, as it determines both the position of active sites and the overall three-dimensional shape of the protein. For instance, the tertiary structure of enzymes is vital for their ability to bind to substrates and catalyze reactions.  

Tertiary Structure of Protein Example  

An example of a protein with a well-defined tertiary structure is myoglobin, a globular protein that stores oxygen in muscle cells. Its compact, globular shape allows it to efficiently bind and release oxygen molecules.  

Protein Structure and Function  

The structure of a protein is intimately connected to its function. The specific shape and folding pattern of a protein enable it to interact with other molecules in precise ways. For example, enzymes have active sites that fit specific substrates, much like a key fits into a lock.  

Proteins carry out a variety of functions within living organisms, including:  

Catalysis: Enzymes accelerate chemical reactions, making them essential for metabolism.  

Transport: Proteins such as hemoglobin are involved in carrying molecules like oxygen throughout the body.  

Support: Structural proteins like collagen provide strength and support to tissues.  

Defense: Antibodies are proteins that protect the body from pathogens.  

Without the correct structure, proteins cannot perform these functions, leading to various diseases and disorders.  

Proteins are vital biomolecules with intricate structures that dictate their functions. Understanding the structure of proteins, from the basic sequence of amino acids to the more intricate tertiary and quaternary structures, is crucial for comprehending their roles in biological processes.  

The ongoing Ebola outbreak in West Africa is serious and scary. Given the intense pressure and mounting fear about this virus, at our lab's weekly journal club meeting I presented a summary of research into the structure and function of proteins from the Ebola virus.

I’m not a virologist so my impression after getting up to speed with Ebola research was amazement at the complexity and versatility of the virus's tiny genome (only 7 genes).  Also I was amazed at its ability to shield itself from the immune system...it's a nasty little thing.

I presented this research from the point of view of a structural biologist who studies how the form of biomolcules is responsible for their function. What this means is that the 3D shape of molecules provides characteristics that determine how they function in cells.

An analogy to everyday life would be how the shape of a car endows this machine with certain properties.  The wheels provide motion, the steering wheel provides control, the seats provide a place for passengers to sit, and so on.  In this same way, the way atoms in biomolecules are arranged in space confers the functional properties that make them molecular machines.

Since Ebola contains only 7 genes, the forces of evolution (reproduce or go extinct) have shaped the virus into using its biomolecular machines in the most effective way to propagate itself.  

The seven proteins in the Ebola genome.

Ebola is like MacGyver. MacGyver was a TV show in the 80s about a guy who could escape any predicament by fashioning tools and devices out of pretty much nothing...duct tape, some pocket lint, dirt from the ground, whatever.  He was Mr. Resourceful.

Not sure how this guy would feel being compared to Ebola, but Ebola proteins are as versatile as he was.

Research into the 3D shapes and functions of Ebola proteins have revealed they are resourceful, multifunctional and dynamic. The proteins adopt different shapes to do different jobs in the life cycle of the virus.

One such multifunctional protein is VP40.  This protein is like the virus' Lego set: it is able to perform different jobs according to its arrangement with itself.  After Ebola infects a cell, the cellular machinery is hijacked into synthesizing more copies of the virus’s genome and viral proteins. One of the jobs of the VP40 molecules is to manipulate the host cell’s reading of the Ebola genome and to do this it adopts a ring structure that is able to recognize and regulate the reading of the code of the viral RNA genome.  

A second job of VP40's is to form long cylinder shaped structures that eventually form the matrix of the virus, which could be considered the "skeleton" of the virus that gives it its distinctive long, spaghetti-like shape. These cylinders of VP40 form on the interior face of the infected cell membrane and package the newly synthesized contents of the progeny Ebola virions (the other Ebola proteins and its RNA genome).  VP40 then “buds” from the cell, stealing part of the infected cell's membrane and packaging the Ebola proteins and genome, thus releasing more Ebola viruses that go on and repeat the infection cycle.

Electron micrograph of an Ebola virion (source: CDC)

Another amazingly cool (in a deadly way) Ebola protein is the glycoprotein (or GP), also known as the spike protein.  This protein is the only one exposed on the exterior of the virus and its job is to contact host cells and begin the process of invasion.  Its second job occurs after the virus is inside the cell (where it is enclosed in a membrane-bound compartment).  GP's second job is to fuse the viral membrane with the membrane of its compartment within the cell.  This causes the interior contents of the virus to spill out where they are able to do further work in the cell and hijack it.

GP is like a Trojan Horse.  Crystal structures have shown it forms a chalice shape and inside the chalice is hidden its tools to perform its work.  These tools are hidden from host cell's immune system. Along with this strategy, the chalice is covered by sugars which are poor antigens (they are not recognized by our immune system).

Artist's impression of the Ebola glycoprotein (pink), imbedded in the virus' membrane (grey).

A final strategy by GP is that multiple versions of it are produced by the hijacked cell and each of them acts as a decoy from the intact, functional GP protein.  Nasty.

This explains just two of the seven Ebola proteins.  Each is versatile, multifunctional and deceptive.  Because of these characteristics Ebola is an amazingly effective killer.

Due to the sheer size of the current outbreak, much-needed resources have been marshaled to develop effective treatments and vaccines.  The research into the 3D form of Ebola proteins has been essential for understanding this virus, guiding drug and vaccine discovery.  For example, the structure of the GP protein identified areas of its 3D structure that are exposed on the exterior of the virus.  This structure has been used to understand how the monoclonal antibody treatment cocktail ZMAb targets GP and therefore is aiding in improving this treatment.  As well, small chemicals have been discovered that block the function of VP35, a protein I didn't discuss here, and stop the virus dead in its tracks.  3D structural studies of VP35 with this molecule may lead to its optimization into an actual drug, but this is very early research at this stage.

Hey.

I was blogging for a while over at blog.1degreebio.org but I decided hey, I deserve my own private blog where I can be in full control of the drivel I feed the world!  Just kidding.  Kinda.

I hope that what I will share will be enlightening and will provoke at least some thoughts in your mind about issues related to science, being a scientist, what science means in our society, and related concepts.

For my day job I work at a researcher working in the field of structural genomics / structural biology.  You can find me easily online, at Researchgate, LinkedIn and Twitter.

In in a nutshell, structural biology is the science of visualizing the most inner workings of organisms and using this information to understand how freakin' amazing life really is.  It's pretty crazy how life operates at the molecular level, and it is this sense of fascination that drives structural biologists.  At least it does drive me.  Understanding the foundations for how life works, atom by atom, molecule by molecule, always fascinates me!

I called this blog "Science Life" because I want to capture much more than my own research.  I will try to post at least once a week on a variety of topics of interest to me and from the goings-on of the scientific community.  I'm passionate about science communication and blogging is such an important tool for scientists to connect with each other and with the public.  I believe it is essential for scientists to engage others if we are to effect societal changes through research.  If only a select few understand our work, what's the point?

I hope to connect with readers interested in topics such as:

what's it like to be a scientist?

how does scientific research work, and how should it work?

what role does science play in our lives and in greater society?

how can we communicate and connect the amazing science being done in research labs to the public on the whole?

how do politics, government, law, technological changes interface with the scientific research enterprise?

I'm also thinking of featuring some snapshots of my personal research in a way that highlights just how cool the stuff I'm doing in the lab really is.   My main research focus is in antibiotic resistance / aka "superbugs" - and these little buggers are crazy smart..or at least we have evolved crazy smart adaptations to overcome our drugs.  More later :)