Protein Conformational Disease: Visit the Facts at a Glance

Abstract

Proteins perform their function for adopting a particular 3D structure, referred as native structure, and failure to fold into the native structure has profound deleterious effects, frequently causing diseases. Such diseases, termed as protein conformational diseases, are a large group of disorders that arise from protein adopting abnormal conformational states. In the past two decades, it has been shown that conformational diseases affect large fraction of human population and present significant challenges to human health. Many protein conformational diseases are multifactorial diseases and result from very complicated molecular mechanisms. The most prominent disease‐associated phenomena of protein conformational diseases are toxic gain of function, loss of function, improper degradation and improper localisation. Furthermore, recent promising therapeutic approaches are developed for treating conformational disease. Key Concepts A remarkable relationship exists between the protein's functionality and specific three‐dimensional structure. The energy landscape in protein folding resembles a rough funnel and proteins could be trapped in the intermediate states, resulting in misfolded proteins. Protein conformational disease refers to the pathology that a protein adopts abnormal conformational states, disturbing the normal role of a protein in the cell. Multiple phenomena including loss of function, toxic gain of function, improper degradation and localisation are associated with protein conformational diseases. Protein conformational disease affects large human populations and developing therapeutic approach is a priority task for better public health.

Pharmacological Chaperones and Protein Conformational Diseases: Approaches of Computational Structural Biology

“…Known as protein conformational diseases, such disorders arise when proteins adopt abnormal conformations. Many people suffer from conformational diseases, significantly challenging human health [ 8 ]. The present review focuses on examples of rare types of conformational diseases, such as (with involved protein in parenthesis): Phenylketonuria (phenylalanine hydroxylase, PAH) [ 9 , 10 ], Alkaptonuria (1,2 homogentisate dioxygenase, HGD) [ 11 , 12 ], Transthyretin-related hereditary amyloidosis (transthyretin, TTR) [ 13 ], and the group of lysosomal storage diseases [ 14 ] including GM1-gangliosidosis (β-galactosidase), Tay-Sachs disease (β-hexosaminidase A), Sandhoff disease (β-hexosaminidases A and B), AB variant of GM2-gangliosidosis (GM2 activator protein), Fabry disease (α-galactosidase A), Gaucher disease (β-glucocerebrosidase), Pompe disease (α-glucosidase), mucopolysaccharidosis IIIC (heparan-α-glucosaminide N-acetyltransferase), and Batten disease (battenin).…”