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A modular protein of epic proportions!

Titin, sometimes known as connectin, is a giant muscle protein, about 30 thousand amino acids long. Its a long filamentous protein that spans half of the muscle sarcomere and has important roles in both muscle contraction and its elasticity. It plays a role in controlling chromosome shape in the cell nucleus. Titin is achored on the Z-disk and M-line in a muscle cell and exerts a passive force that keeps the sarcomere components aligned.

Titin is a modular protein, composed of approximately 300 fibronectin type III (FnIII) and immunoglobulin type (Ig) domains (see Immunoglobulin Superfamily). The FnIII domains are exclusively located in the A-band of the molecule and the Ig domains are found along the whole length of titin. The I-band contains PEVK domains (domains that are more than 70% proline, glutamic acid, valine or lysine) bracketed by Ig domains. Because of the high concentration of positively charged residues such as lysine and glutamic acid, the PEVK domain remains largely in a random coil state, while the Ig and FnIII domains form beta-sandwich folds. Normally, when the protein is stretched, the PEVK domain unfolds and elongates. Under extreme stress, the Ig domains will also begin to unfold.

Using single molecule techniques such as atomic force microscopy (AFM), it is believed that the FnIII and Ig domains can fold independently of each other. AFM on a single protein can be done by attaching a probe to one end of titin, and attaching the other end of titin to some solid substrate. As increasing force is applied to the molecule, the domains pop open individually, resulting in an oscillating force vs distance curve. Forces on the order of 100 picoNewtons must be exerted before unfodling begins to occur. This is higher than most proteins which do not have to deal with mechanical strain as part of their native function. Additionally, molecular dynamics simulations where the applied pulling force is included in the model, have tried to isolate key interactions that give the molecule its tensile strength and elasticity. The current ideas seem to suggest that weak interstrand hydrogen bonds contribute the bulk of strength to the Ig domains.

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