Proteins: Structure, Function, and Amyloidosis
Proteins and Their Functions
Proteins are large biological molecules composed of one or more chains of amino acids linked by peptide bonds. They are essential components of virtually every cell and participate in almost all biological processes.
Proteins can be classified according to their principal functions:
The biological function of a protein depends not only on its amino acid sequence but also on its precise three-dimensional structure. (NCBI)
Proteins in Blood
The major proteins found in blood plasma are albumin, globulins, and fibrinogen. Hemoglobin is also one of the most abundant proteins in blood, but unlike plasma proteins, it is located predominantly inside red blood cells (erythrocytes).
Albumin is the most abundant protein in human plasma and accounts for approximately 50–60% of total plasma protein. It is synthesized by hepatocytes in the liver. (NCBI)
Albumin has several important functions:
A reduced serum albumin concentration may occur, for example, in advanced liver disease, severe inflammation, malnutrition, or increased protein loss through the kidneys or gastrointestinal tract.
Levels of Protein Structure
Protein structure is traditionally divided into four hierarchical levels: primary, secondary, tertiary, and quaternary structure. (NCBI)
The primary structure describes the precise linear sequence of amino acids in a polypeptide chain.
The amino acid sequence is genetically determined and has a major influence on all higher levels of protein structure. Even the substitution of a single amino acid can sometimes significantly alter protein function.
The secondary structure describes local, regularly organized folding patterns within the polypeptide chain.
These structures are stabilized mainly by hydrogen bonds between components of the peptide backbone.
The two most important forms are:
α-helix:
The polypeptide chain coils into a spiral structure, usually a right-handed helix.
β-pleated sheet:
Segments of the polypeptide chain lie next to each other and are connected through hydrogen bonds, producing a sheet-like structure.
Both α-helices and β-sheets are normal structural elements of many proteins. (PubMed Central (PMC))
The tertiary structure represents the overall three-dimensional shape of a single polypeptide chain.
It results from interactions between amino acid side chains, including:
The tertiary structure is particularly important because the biological activity of many proteins depends directly on their three-dimensional configuration. For example, an enzyme must have the correct shape of its active site in order to bind its substrate. (NCBI)
Some functional proteins consist of several individual polypeptide chains, called subunits.
The quaternary structure describes how these separate protein subunits interact and assemble into a functional protein complex. Each individual subunit already possesses its own tertiary structure. (PubMed Central (PMC))
A classic example is hemoglobin, which consists of four protein subunits.
Protein Folding and Misfolding
Correct protein folding is essential for normal protein function.
After a protein has been synthesized, the amino acid chain must adopt its specific three-dimensional structure. Cells contain specialized proteins called molecular chaperones, which assist other proteins in folding correctly and help prevent inappropriate aggregation.
Incorrectly folded proteins are normally recognized and removed by cellular quality-control systems, including the ubiquitin–proteasome system and lysosomal/autophagic pathways.
However, these protective mechanisms can sometimes fail. Misfolded proteins may then accumulate and form insoluble aggregates.
One particularly important type of protein aggregate is amyloid.
Amyloid consists of abnormally folded proteins that aggregate into highly organized, insoluble fibrils. A characteristic structural feature of amyloid fibrils is their high content of β-sheet structures.
These fibrils may accumulate in the extracellular space of tissues and organs.
Amyloidosis refers to a heterogeneous group of diseases characterized by the deposition of these misfolded proteins as amyloid fibrils.
The deposits are difficult for the body to eliminate and progressively interfere with normal tissue architecture and organ function. Amyloidosis can be localized, affecting only one organ or tissue, or systemic, involving several organs. (Merck Manuals)
More than 30 different precursor proteins are known to be capable of forming amyloid, but three systemic forms are particularly important:
AL amyloidosis, ATTR amyloidosis, and AA amyloidosis.
AL amyloidosis (immunoglobulin light-chain amyloidosis) is one of the most important forms of systemic amyloidosis.
It is caused by an abnormal clone of plasma cells in the bone marrow that produces excessive amounts of monoclonal immunoglobulin light chains or light-chain fragments.
These light chains have an increased tendency to misfold, aggregate, and form amyloid fibrils. The fibrils are subsequently deposited in tissues and organs. (ASH Publications)
Commonly affected organs include:
Cardiac involvement is particularly important because amyloid infiltration of the myocardium can lead to a restrictive/infiltrative cardiomyopathy and progressive heart failure.
Renal involvement frequently causes proteinuria, sometimes progressing to nephrotic syndrome and renal failure.
AL amyloidosis is related to plasma-cell disorders and may occur independently or in association with conditions such as multiple myeloma.
Diagnosis typically includes testing for monoclonal proteins and free light chains as well as demonstration and characterization of amyloid in tissue. Correct identification of the amyloid protein is essential because treatment differs fundamentally between AL and ATTR amyloidosis. (Merck Manuals)
Transthyretin (TTR) is predominantly synthesized in the liver. It circulates as a tetrameric transport protein and is involved in the transport of thyroxine (T4) and retinol through interaction with retinol-binding protein.
Destabilization of the TTR tetramer can cause it to dissociate into monomers. These monomers can subsequently misfold and aggregate into amyloid fibrils.
The resulting disease is known as transthyretin amyloidosis (ATTR amyloidosis). (Merck Manuals)
Two major forms are distinguished.
Hereditary ATTR amyloidosis — ATTRv
In variant or hereditary ATTR amyloidosis (ATTRv), mutations in the TTR gene destabilize the protein and increase its tendency to form amyloid.
The disease is inherited in an autosomal-dominant manner, although disease penetrance varies considerably.
Depending on the specific mutation, patients may predominantly develop:
or a combination of these manifestations. (PubMed Central (PMC))
Wild-type ATTR amyloidosis — ATTRwt
In wild-type ATTR amyloidosis (ATTRwt), the TTR gene is normal.
Instead, normal wild-type TTR becomes increasingly prone to misfolding and aggregation with advancing age.
ATTRwt predominantly affects the heart and is now increasingly recognized as an important cause of heart failure in older individuals. (JACC)
Amyloid may also accumulate in ligaments and tendons. Consequently, conditions such as bilateral carpal tunnel syndrome and lumbar spinal stenosis can precede the diagnosis of cardiac ATTR amyloidosis by several years. (JACC)
AA Amyloidosis
AA amyloidosis is associated with persistent inflammatory activity.
During inflammation, the liver produces large amounts of the acute-phase protein serum amyloid A (SAA). When SAA concentrations remain elevated for prolonged periods, fragments of the protein may misfold and form amyloid fibrils. (Merck Manuals)
AA amyloidosis may therefore occur in association with chronic inflammatory or infectious diseases.
The kidneys are particularly frequently affected.
Renal amyloid deposition can cause:
Controlling the underlying inflammatory disease and thereby reducing serum amyloid A production is therefore a central principle in the prevention and treatment of AA amyloidosis.
The Three Major Systemic Amyloidoses at a Glance
Type | Amyloid precursor | Main underlying mechanism | Frequently affected organs |
AL | Immunoglobulin light chains | Clonal plasma-cell disorder | Heart, kidneys, nerves, liver |
ATTRv | Mutated transthyretin | Inherited TTR mutation | Nerves, heart |
ATTRwt | Wild-type transthyretin | Age-related TTR misfolding | Primarily heart; also tendons/ligaments |
AA | Serum amyloid A | Chronic inflammation/infection | Primarily kidneys |
An important clinical point is that amyloidosis is not a single disease. The underlying amyloid-forming protein must be identified because prognosis and treatment differ substantially among AL, ATTR, AA, and other forms. (Merck Manuals)