Abstract
For a protein to function appropriately, it must first achieve its proper conformation and location within the crowded environment inside the cell. Multiple chaperone systems are required to fold proteins correctly. In addition, degradation pathways participate by destroying improperly folded proteins. The intricacy of this multisystem process provides many opportunities for error. Furthermore, mutations cause misfolded, nonfunctional forms of proteins to accumulate. As a result, many pathological conditions are fundamentally rooted in the protein-folding problem that all cells must solve to maintain their function and integrity. Here, to illustrate the breadth of this phenomenon, we describe five examples of protein-misfolding events that can lead to disease: improper degradation, mislocalization, dominant-negative mutations, structural alterations that establish novel toxic functions, and amyloid accumulation. In each case, we will highlight current therapeutic options for battling such diseases.
Highlights
Proteins are the molecular machines that control our most vital cellular functions
Protein folding is made even more difficult by the crowded environment of the cell, where proteins must assume their correct conformation while being constantly bombarded by high-energy collisions with neighboring proteins (Ellis and Minton, 2006)
The examples we provide include diseases caused by loss-of-function mutations and diseases resulting from gain-of-function mechanisms (mutations that cause a toxic novel function, dominant-negative mutations and Disease Models & Mechanisms (2014) doi:10.1242/dmm
Summary
Proteins are the molecular machines that control our most vital cellular functions. To fulfill its role, a protein must first fold into its correct three-dimensional structure, assuming complicated tertiary and sometimes quaternary conformations. Many misfolded proteins involved in disease contain one or more mutations that destabilize the correct fold and/or stabilize a misfolded state.
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