The serum amyloid P component (SAP) is the identical serum form of the amyloid P component (AP), a 25 kDa pentameric protein first identified as the pentagonal constituent of in vivo pathological deposits called "amyloid". [5] APCS is its human gene. [6]
SAP makes up 14% of the dry mass of amyloid deposits [7] and is thought to be an important contributor to the pathogenesis of a related group of diseases called the Amyloidoses. [8] These conditions are characterised by the ordered aggregation of normal globular proteins and peptides into insoluble fibres, which disrupt tissue architecture and are associated with cell death. SAP is thought to decorate and stabilise aggregates by preventing proteolytic cleavage and hence inhibiting fibril removal via the normal protein scavenging mechanisms. [9] This association is utilised in the routine clinical diagnostic technique of SAP scintigraphy whereby radio-labelled protein is injected into patients to locate areas of amyloid deposition. [10] The SAP-amyloid association has also been identified as a possible drug target for anti-amyloid therapy, with the recent development and first stage clinical trials of a compound called CPHPC (R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxohexanoyl] pyrrolidine-2-carboxylic acid), a small molecule able to strip AP from deposits by reducing levels of circulating SAP. [11]
SAP is a member of the pentraxins family, characterised by calcium-dependent ligand binding and a distinctive flattened β-jellyroll structure similar to that of the legume lectins. [12] The name "pentraxin" is derived from the Greek words for five (penta) and berries (ragos), relating to the radial symmetry of five monomers forming a ring approximately 95 across and 35 deep. Human SAP has 51% sequence homology with C-reactive protein (CRP), a classical acute phase response plasma protein, and is a more distant relative to the "long" pentraxins such as PTX3 (a cytokine-modulated molecule) and several neuronal pentraxins. Both SAP and CRP are evolutionary conserved in all vertebrates and are also found in distant invertebrates such as the horseshoe crab (Limulus polyphemus). [13]
C-reactive protein (CRP) is an annular (ring-shaped) pentameric protein found in blood plasma, whose circulating concentrations rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin-6 secretion by macrophages and T cells. Its physiological role is to bind to lysophosphatidylcholine expressed on the surface of dead or dying cells in order to activate the complement system via C1q.
Amyloids are aggregates of proteins characterised by a fibrillar morphology of typically 7–13 nm in diameter, a β-sheet secondary structure and ability to be stained by particular dyes, such as Congo red. In the human body, amyloids have been linked to the development of various diseases. Pathogenic amyloids form when previously healthy proteins lose their normal structure and physiological functions (misfolding) and form fibrous deposits within and around cells. These protein misfolding and deposition processes disrupt the healthy function of tissues and organs.
Amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue. There are several non-specific and vague signs and symptoms associated with amyloidosis. These include fatigue, peripheral edema, weight loss, shortness of breath, palpitations, and feeling faint with standing. In AL amyloidosis, specific indicators can include enlargement of the tongue and periorbital purpura. In wild-type ATTR amyloidosis, non-cardiac symptoms include: bilateral carpal tunnel syndrome, lumbar spinal stenosis, biceps tendon rupture, small fiber neuropathy, and autonomic dysfunction.
Transthyretin (TTR or TBPA) is a transport protein in the plasma and cerebrospinal fluid that transports the thyroid hormone thyroxine (T4) and retinol to the liver. This is how transthyretin gained its name: transports thyroxine and retinol. The liver secretes TTR into the blood, and the choroid plexus secretes TTR into the cerebrospinal fluid.
Amylin, or islet amyloid polypeptide (IAPP), is a 37-residue peptide hormone. It is co-secreted with insulin from the pancreatic β-cells in the ratio of approximately 100:1 (insulin:amylin). Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels.
Bence Jones protein is a monoclonal globulin protein or immunoglobulin light chain found in the urine, with a molecular weight of 22–24 kDa. Detection of Bence Jones protein may be suggestive of multiple myeloma, or Waldenström's macroglobulinemia.
β2 microglobulin (B2M) is a component of MHC class I molecules. MHC class I molecules have α1, α2, and α3 proteins which are present on all nucleated cells. In humans, the β2 microglobulin protein is encoded by the B2M gene.
Pentraxins (PTX), also known as pentaxins, are an evolutionary conserved family of proteins characterised by containing a pentraxin protein domain. Proteins of the pentraxin family are involved in acute immunological responses. They are a class of pattern recognition receptors (PRRs). They are a superfamily of multifunctional conserved proteins, some of which are components of the humoral arm of innate immunity and behave as functional ancestors of antibodies (Abs). They are known as classical acute phase proteins (APP), known for over a century.
Cardiac amyloidosis is a subcategory of amyloidosis where there is depositing of the protein amyloid in the cardiac muscle and surrounding tissues. Amyloid, a misfolded and insoluble protein, can become a deposit in the heart's atria, valves, or ventricles. These deposits can cause thickening of different sections of the heart, leading to decreased cardiac function. The overall decrease in cardiac function leads to a plethora of symptoms. This multisystem disease was often misdiagnosed, with diagnosis previously occurring after death during autopsy. However, recent advancements of technologies have increased the diagnosis of the disease. Cardiac amyloidosis has multiple sub-types including light chain, familial, and senile. One of the most studied types is light chain cardiac amyloidosis. Prognosis depends on the extent of the deposits in the body and the type of amyloidosis. New treatment methods are actively being researched in regards to the treatment of heart failure and specific cardiac amyloidosis problems.
Serum amyloid A (SAA) proteins are a family of apolipoproteins associated with high-density lipoprotein (HDL) in plasma. Different isoforms of SAA are expressed constitutively at different levels or in response to inflammatory stimuli. These proteins are produced predominantly by the liver.
In medicine, proteinopathy, or proteopathy, protein conformational disorder, or protein misfolding disease, is a class of diseases in which certain proteins become structurally abnormal, and thereby disrupt the function of cells, tissues and organs of the body. Often the proteins fail to fold into their normal configuration; in this misfolded state, the proteins can become toxic in some way or they can lose their normal function. The proteinopathies include such diseases as Creutzfeldt–Jakob disease and other prion diseases, Alzheimer's disease, Parkinson's disease, amyloidosis, multiple system atrophy, and a wide range of other disorders. The term proteopathy was first proposed in 2000 by Lary Walker and Harry LeVine.
Pentraxin-related protein PTX3 also known as TNF-inducible gene 14 protein (TSG-14) is a protein that in humans is encoded by the PTX3 gene.
Serum amyloid A protein is a protein that in humans is encoded by the SAA2 gene.
Serum amyloid A1 (SAA1) is a protein that in humans is encoded by the SAA1 gene. SAA1 is a major acute-phase protein mainly produced by hepatocytes in response to infection, tissue injury and malignancy. When released into blood circulation, SAA1 is present as an apolipoprotein associated with high-density lipoprotein (HDL). SAA1 is a major precursor of amyloid A (AA), the deposit of which leads to inflammatory amyloidosis.
Leukocyte cell-derived chemotaxin-2 (LECT2) is a protein first described in 1996 as a chemotactic factor for neutrophils, i.e. it stimulated human neutrophils to move directionally in an in vitro assay system. The protein was detected in and purified from cultures of Phytohaemagglutinin-activated human T-cell leukemia SKW-3 cells. Subsequent studies have defined LECT2 as a hepatokine, i.e. a substance made and released into the circulation by liver hepatocyte cells that regulates the function of other cells: it is a hepatocyte-derived, hormone-like, signaling protein.
Collagen alpha-1(XXV) chain is a protein that in humans is encoded by the COL25A1 gene.
AA amyloidosis is a form of amyloidosis, a disease characterized by the abnormal deposition of fibers of insoluble protein in the extracellular space of various tissues and organs. In AA amyloidosis, the deposited protein is serum amyloid A protein (SAA), an acute-phase protein which is normally soluble and whose plasma concentration is highest during inflammation.
Sir Mark Brian Pepys is a South African-born British academic of medicine. He was until 2011 Professor of Medicine at University College London and Head of Medicine at the Hampstead Campus and the Royal Free Hospital.
CPHPC ((R)-1-{6-[(R)-2-carboxypyrrolidin-1-yl]-6-oxohexanoyl}pyrrolidine-2-carboxylic acid) is a proline-derived small molecule able to strip amyloid P (AP) from deposits by reducing levels of circulating serum amyloid P (SAP). The SAP-amyloid association has also been identified as a possible drug target for anti-amyloid therapy, with the recent development and first stage clinical trials of CPHPC for amyloidosis.
A SAP scan is a type of nuclear medicine imaging test which uses iodine-123 (123I) and serum amyloid P component (SAP) to diagnose amyloidosis.
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