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The signal hypothesis is a fundamental concept in cell biology that explains how proteins are directed to their proper cellular locations during and after their synthesis. It was first proposed by Günter Blobel in the 1970s and later experimentally validated, earning him the Nobel Prize in Physiology or Medicine in 1999. According to the signal hypothesis, proteins destined for specific organelles, such as the endoplasmic reticulum (ER), mitochondria, chloroplasts, or for secretion outside the cell, contain a short stretch of amino acids known as a signal sequence. This signal sequence acts as a “postal code” that guides the ribosome-protein complex to the correct cellular compartment, ensuring that proteins reach their functional site efficiently. The process begins in the cytosol, where ribosomes synthesize proteins based on mRNA templates. Proteins that are meant to remain in the cytosol lack a signal sequence and are released directly into the cytoplasm upon completion. In contrast, proteins targeted to the ER contain an N-terminal signal sequence, typically 15–30 amino acids long, rich in hydrophobic residues. As the nascent polypeptide emerges from _____ ____ _________ _____ ________.
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