The sterol regulatory element–binding protein (SREBP) is the most well-known example of regulated intramembrane proteolysis (RIP). SREBP is a transmembrane protein found in the endoplasmic reticulum membrane. When cellular cholesterol levels are low, RIP occurs in SREBP, resulting in the cleavage of a fragment that is then transported to the nucleus. In the nucleus, this fragment activates genes responsible for cholesterol biosynthesis.

Hormones transmit signals to effector proteins through intracellular signaling pathways when they bind to plasma membrane receptors. However, when hormones bind to nuclear or cytosolic receptors, they primarily regulate gene expression to transmit signals. Signaling pathways have the capability to amplify and integrate signals, as well as downregulate and desensitize signals. This enables the reduction or termination of the response, even in the presence of the hormone.

Alzheimer’s disease is a progressive neurodegenerative brain disease that affects approximately 44 million people worldwide. It is characterized by the formation of amyloid plaques. Amyloid β-protein precursor (APP) undergoes regulated intramembrane proteolysis in Alzheimer’s disease, leading to the accumulation of amyloid β-protein (Aβ). These Aβ proteins form amyloid plaques, which contribute to the pathogenesis of the disease. APP is a type I transmembrane protein that undergoes sequential proteolysis by β-secretase and γ-secretase after ectodomain shedding. This process produces Aβ40 and Aβ42 peptides, which accumulate in individuals with Alzheimer’s disease. Missense mutations in presenilins, proteins that regulate γ-secretase protease activity, enhance the production of Aβ42, which is more hydrophobic and prone to aggregation into amyloid fibrils compared to the more abundant Aβ40 protein.

Intracellular signaling molecules, known as second messengers, include small molecules such as cAMP, cGMP, Ca++, and diacylglycerol. These molecules relay the signal within signaling pathways, which often consist of numerous small molecules forming complex networks within the cell. Some intracellular signaling proteins pass the signal directly to another protein by phosphorylating a target or inducing an allosteric change through binding. These proteins function as reversible molecular switches, transitioning between an inactive and active form until another signaling molecule reverses the process. Reversibility plays a central role in many signaling pathways. Activation is often achieved by reversing inhibition, such as the thyroid hormone receptor being bound to an inhibitory protein in the absence of a signal.

Signaling complexes, composed of multiple physically interacting proteins, enhance the speed, efficiency, and specificity of signaling. Enzymes or ion channels are often involved in transducing the signal into a different chemical form while simultaneously amplifying the signal. This can occur through the production of additional signaling molecules or activation of downstream signaling proteins. For example, adenylyl cyclase, the enzyme responsible for cAMP production, transduces a signal by receptor activation of G proteins and amplifies the signal through the generation of large amounts of cAMP. Other types of signaling proteins integrate multiple signals, while some transport the signal from one cellular region to another, such as translocating from the cytosol to the nucleus.
Fig. 3.6 ). The best characterized example of RIP is the sterol regulatory element–binding protein (SREBP), a transmembrane protein expressed in the membrane of the endoplasmic reticulum. When cellular cholesterol levels are low, SREBP undergoes RIP, and the proteolytically cleaved fragment is translocated into the nucleus, where it transcriptionally activates genes that promote cholesterol biosynthesis.
When hormones bind to plasma membrane receptors, signals are relayed to effector proteins via intracellular signaling pathways. When hormones bind to nuclear or cytosolic receptors, they relay signals primarily through regulation of gene expression. Signaling pathways can amplify and integrate signals but can also downregulate and desensitize signals, reducing or terminating the response, even in the continued presence of hormone.
Alzheimer’s disease, a progressive neurodegenerative brain disease characterized by the formation of amyloid plaques, affects approximately 44 million people worldwide. In Alzheimer’s disease, regulated intramembrane proteolysis of amyloid β-protein precursor (APP) causes the accumulation of amyloid β-protein (Aβ), which forms amyloid plaques that contribute to the pathogenesis of Alzheimer’s disease. APP is a type I transmembrane protein (i.e., its spans the membrane only once). After ectodomain shedding, its sequential proteolysis by β-secretase and γ-secretase produces the Aβ40 and Aβ42 peptides that are normally produced throughout life but accumulate in individuals with Alzheimer’s disease. Missense mutations in presenilins, proteins that regulate γ-secretase protease activity, enhance the production of Aβ42, which is more hydrophobic and prone to aggregation into amyloid fibrils than is the more abundant Aβ40 protein.
Intracellular signaling molecules—so-called second messengers (the first messenger of the signal is the ligand that binds to the receptor)—include small molecules such as cAMP, cGMP, Ca++, and diacylglycerol. Signaling pathways often include dozens of small molecules that form complicated networks within the cell (Fig. 3.7 ). Some proteins in the intracellular signaling pathways relay the signal by passing the message directly to another protein (e.g., by phosphorylating a target, or by binding and causing an allosteric change). Such intracellular signaling proteins act as reversible molecular switches: When a signal is received, they switch from an inactive to an active form or vice versa, until another signaling molecule reverses the process. This principle of reversibility is central to many signaling pathways. In many cases, activation is achieved by reversing inhibition: For example, the thyroid hormone receptor is bound to an inhibitory protein in the absence of signal.
Signaling complexes, composed of multiple proteins that interact physically, enhance the speed, efficiency, and specificity of signaling. Many proteins, usually enzymes or ion channels, transduce the signal into a different chemical form and simultaneously amplify the signal either by producing large amounts of additional signaling molecules or by activating a large number of downstream signaling proteins. For example, adenylyl cyclase, the enzyme that makes cAMP, transduces a signal (receptor activation of G proteins) and amplifies the signal by generating large amounts of cAMP. Other types of signaling proteins include those that integrate multiple signals. Other proteins carry the signal from one region of the cell to another: for example, by translocating from the cytosol to the nucleus.