Structural Biochemistry/Protein Misfolding and Human Disease
Protein misfolding is a particularly insidious contributor to human disease. During the complex kinetic and thermodynamic choreography required for a protein to achieve its proper structure and function, missteps can occur by a variety of mechanisms. Coupled with a breakdown in the protein quality control systems designed to correct or remove misfolded proteins (39), loss- or gain-of-function phenotypes can lead to a sobering number of diseases (39, 40). Two aspects of protein misfolding are reviewed. The remarkable hair-trigger conformational reorganization essential to the mechanism of protease inactivation by the serpins can spontaneously misfire as graphically described by Gooptu & Lomas (41). Inappropriate autoreorganization enhanced by specific mutations can lead to inactive forms of the serpin, resulting in loss-of-function diseases, which in this system result in an increase in the activity of the corresponding protease. In certain cases, serpin polymers can form, resulting in toxic gain-of-function diseases—serpinopathies. The structural clarity, and relative simplicity, of the serpin system lends itself as a model for understanding other diseases of protein aggregation. Approaches to design small-molecule inhibitors of serpin polymerization are also emerging (41). Proteins or peptides convert from their usual soluble form into fibrillar aggregates. This shift in conformation is detrimental to proteins as it gives rise to many pathological problems. Misfolding results when formation of thread-like aggregates called amyloid fibrils begin taking shape. Failure for polypeptides to remain in their functional conformational state results in misfolding. This misfolding impairment reduces the proteins’ ability to perform its task in a cell.
Reasons for Misfolding Impairment Misfolding impairment usually arises from the degradation of the endoplasmic reticulum or the wrong transportation of that protein. But the most common reason for misfolding is due to the fact that proteins or peptide convert from their usual soluble form into fibrillar aggregates, or amyloid fibrils. Amyloid fibrils are formed in “cross-β” arrangements of their polypeptide chain.
Discovery of Components of the Amyloid Fibrils Components of these amyloid fibrils have been extracted and purified in numerous experiments in order for scientists to understand the cause of the misfolding. These fibrils are imaged using electron microscopy and reveals that they usually consist of 2-6 protofilaments that twist together to from a rope-like conformation. Further x-ray diffraction data shows that these molecular are arranged in β-strands that run perpendicular to the long axis of the fibril. Researchers have found that metal ions, glycosaminoglycans, serum amyloid P component, apolipoprotein E and collagen make up the bulk of the protein component associated with amyloid diseases. In recent years, Solid-State NMR (SSNM) has been used to analyze the amyloid β structure. SSNMR has identified the region of the C-terminal of the protein that is involved heavily in the core of the fibril. Torsion angles and internuclear distances have also been able to be measured and it provided valuable insight on the degree of uniformity the fibrils possess, which has only been associated with crystalline materials. High resolution X-ray Crystallography has also been used to determine the structure of these amyloid fibrils. Data collected from crystallography further supports the parallel β-strands alignment in the protein. The β-sheets in the protein suggests that initiate interaction could represent crystal formation rather than the protein in fribrillar state.
Amyloid Formation Research heavily supports that amyloid fibril formation is due to nucleated growth mechanism. For example, addition of fibrillar species under aggregated conditions causes a lag phase to appear. It is clear that the lag phase is the stage in which β-rich species provide nuclei for formation of mature fibrils.
Diseases caused by Protein Misfolding Some prevalent human diseases that arise from misfolding include Alzheimer’s, Parkinson’s, Huntington’s, dementia and Type II diabetes. Conditions of these diseases are predominantly sporadic (85%), and hereditary (10%), although transmissible (5%) has been recorded as well.
With this in mind, scientists still have not developed a full understanding as to why protein misfolding occurs. Much more research is still needed in this field and solving this mystery could lead to rise in potential drug treatments for these disease.
Chit, Dobson. “Protein Misfolding, Functional Amyloid, and Human Disease. Annual Review of Biochemistry. Vol. 75: 333-366 (Volume publication date July 2006) DOI: 10.1146/annurev.biochem.75.101304.123901.