Chaperones

Chaperones are proteins that "help" newly synthesized proteins to fold correctly (folding assistants). The term "chaperones" was chosen "because they protect immature proteins from harmful confomations". Chaperones are heterogeneous (unrelated) but functionally related protein complexes that are characterized by their functional commonality, i.e. protein folding (Brandvold KR et al. 2015). Their members evolved at very different times during evolution.

Newly synthesized proteins organize themselves in their specific, native, functional conformation. This is basically laid out in the primary structure, the sequence of amino acids. Smaller proteins can spontaneously fold in the correct way (a classic example of spontaneous folding is ribonuclease). Larger, complex, unfolded proteins require "aids" to fold correctly.

Unfolded proteins have highly reactive hydrophobic side chains. These can come together with other hydrophobic molecules or other protein chains to form completely disordered protein aggregates. Such protein aggregates lose their biological function and represent useless or cell-damaging protein waste. To avoid this process, which is unphysiological for the cell, the cell uses a complex, highly conserved protein machinery, the chaperones ("molecular red cross").

Chaperones prevent the aggregation of incompletely folded protein chains by shielding the exposed hydrophobic amino acid segments. After successful chaperone-assisted folding, these hydrophobic segments are hidden inside the protein. Chaperones are then only active until the folded, native state of the protein is reached. In this way, chaperones can distinguish precisely between unfolded and folded proteins. Chaperones act like a catalyst by assisting the correct folding of proteins without becoming part of the structure themselves.

Some chaperones exhibit an increased synthesis rate at unphysiologically high temperatures. They therefore belong to the classic heat shock proteins(heat shock is defined as a "brief increase in temperature to approx. 42°C for 5 minutes". Heat shock proteins are proteins that are released during a heat shock).

Chaperonins are a subgroup of molecular chaperones. In eukaryotes, these are localized exclusively in the mitochondria. Mutations in the HSPD1 gene , which codes for chaperonins, are responsible for hereditary forms of spastic spinal paralysis and leukodystrophy.

Chaperonins form large, cylindrical, approximately 14 nm wide and 15-16 nm high complexes (structure comparable to a donat). In their cavities they assist the folding of proteins. Chaperonins are expressed constitutively, for example in stress situations of the cell, e.g. at elevated temperatures (heat shock proteins).

Chaperones are medically relevant in diseases in which misfolded proteins and their accumulation lead to cell damage. Creutzfeldt-Jakob disease (CJD), Alzheimer's disease and various forms of cutaneous and systemic amyloidosis are important examples of "protein misfolding".

Chaperones may play a role in triggering the reactions in "cold-induced autoimmunological syndromes" (see cold urticaria below). It is conceivable that the mutations underlying FCAS lead to misfolded proteins that are recognized by the temperature-sensitive chaperone HSPA8 (=syn. HSC70; see HSPA8 gene below). At 37 °C, HSPA8 would interact with the mutant proteins and keep them inactive. Lower temperatures could lead to a loss of this interaction due to a conformational change of HSPA8. HSPA8 may act as a cold sensor in various pathological conditions where symptoms worsen at low temperatures (Raghawan AK et al. 2011).

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