modulator proteins

Modulator proteins regulate the activity of other proteins.

Calmodulin (Ca2+-regulated modulator protein, CaM) is a ubiquitous eukaryotic intracellular calcium receptor that regulates the biological activities of many cellular proteins and transmembrane ion transporters.

Calmodulin possess four EF-hand domains that alter conformation upon binding calcium ions. Calcium ions bind to the EF-loop region, shifting the relative positions of the EF-alpha helices. (The other group of proteins that depend on calcium ions for their function belong to the annexin family, which bind calcium and phospholipids). In the absence of calcium, the α-helices in the EF-hand motif of calmodulin are in the closed conformation, almost parallel to each other. When the intracellular calcium level rises, Ca2+ ions bind to calmodulin, causing calmodulin to open into a dumbell shape and increasing CaM's binding affinity. (Nine of CaM's 148 aa residues are methionines, and 8 of these 9 Met are directly involved in binding to all target peptides.) The open conformation Ca2+-calmodulin complex binds target proteins, initiating various signaling cascades. Over a hundred proteins are known to bind calmodulin (above left are three). Calmodulin is essential for cell-cycle progression through mitosis. []molecule of month[]

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PH family

The pleckstrin homology (PH) domain family includes proteins with the PH domain, which is a 100-120 aa module found in a multitude of intracellullar proteins with widepread functions. Many proteins containing PH domains participate in signaling cascades. Other classes of proteins carry a PH domain, including cytoskeletal proteins such as spectrin. [w]

The inositol phospolipids are particularly effective in specific binding to PH domains of cellular proteins. Phosphatidylinositol is an important lipid, both as a participant in essential metabolic processes and as a key membrane constituent. In addition to their role as negatively charged building blocks of membranes, the inositol phospolipids (including the phosphatidylinositol phosphates, or 'polyphosphoinositides') appear to have crucial roles in interfacial binding of proteins and in the regulation of proteins at the cell interface.

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tags [Proteins]
[pleckstrin homology domain] [signaling] [phosphatidylinositol]

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scaffold proteins

Scaffold proteins either hold protein kinases in a latent state close to their activating cell-surface receptors, or facilitate flow of activation from one kinase to the next kinase in a signaling cascade.

The A kinase anchoring proteins (AKAPs) are prototypical scaffold proteins that organize the protein kinases and phosphatases that regulate serine/threonine phosphorylation: 'Multiprotein signaling networks create focal points of enzyme activity that disseminate the intracellular action of many hormones and neurotransmitters. Accordingly, the spatio-temporal activation of protein kinases and phosphatases is an important factor in controlling where and when phosphorylation events occur. Anchoring proteins provide a molecular framework that orients these enzymes towards selected substrates. A-kinase anchoring proteins (AKAPs) are signal-organizing molecules that compartmentalize the cAMP dependent protein kinase, phosphodiesterases, and a variety of enzymes that are regulated by second-messengers.'[s].

In an example of scaffold mediated assembly of signaling pathways, Jip1 has separate binding sites for Jnk, and for the upstream kinases MKK7 (MAPKK), MLK3 (MAPK), and HPK1, enabling Jip1 to act as a scaffold for the mammalian Jnk MAPK cascade. Jip1 also possesses SH3 and PTB domains that can tether the complex to additional proteins participating in upstream activation or localization. B

ERK MAPK docks to target proteins and phosphorylates the substrate, Rsk1.

The regulatory cyclin A subunit of CDK2 binds substrates with a conserved RXL motif, such as p107.

The AKAP protein Yotiao binds the NMDA receptor, inactive PKA, and active PP1. Thus, Yotiao brings together components that repress resting NMDA receptor and enhance channel activation.[s]

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signaling proteins

Proteins and other molecules serve one or more of several types of function in signaling networks:
● cell surface
_ ● ion channels
_ ● receptor proteins
__ ● latent gene regulatory proteins
● intracellular
_ ● 'signaling' enzymes
_ ● adaptor proteins
_ ● amplifier proteins
_ ● anchoring proteins
_ ● bifurcation proteins
_ ● coincidence detectors
_ ● effector proteins
_ ● mediator molecules
_ ● messenger proteins
_ ● modulator proteins
_ ● relay proteins
_ ● scaffold proteins
_ ● second messengers
_ ● transducer proteins

Adaptor proteins link the components of signaling pathways by acting as accessories to the chief proteins in a signal transduction pathway.

Amplifier proteins are usually either enzymes or ion channels. Amplifiers increase the received signal by producing large amounts of small intracellular second messengers or by activating large numbers of downstream intracellular signaling proteins. Multiple amplification steps in a relay chain are often referred to as a signaling cascade.

Anchor proteins provide a molecular framework that orients these enzymes towards selected substrates. A-kinase anchoring proteins (AKAPs) are signal-organizing, scaffold proteins that compartmentalize the cAMP dependent protein kinase, phosphodiesterases, and a variety of enzymes that are regulated by second-messengers.

Bifurcation proteins spread the signal from one signaling pathway to others.

Coincidence detectors are signaling enzymes that are only activated by several different signals occurring together. For example, cAMP-generating adenylyl (adenylate) cyclases are modulated by G-proteins, forskolin, Ca2+/calmodulin, and other class-specific substrates.

Non-genetic classes of regulatory proteins include those target, effector proteins that are involved in special cellular functions such as signaling as receptor proteins and pumps, adhesion, chemotaxis, cellular transport and active transport, and metabolic regulation, including enzymatic action and protein degradation. Effector molecules bring about regulation by binding other molecules, and genetic effector molecules can participate in the regulation of gene expression. Modulator molecules bind to a regulatory sites during allosteric modulation, where effectors act as activators or inhibitors. (Allosteric proteins have an active (catalytic) site and an allosteric (effector) site.) Effector proteins regulate the activity of other proteins.

Integrator proteins integrate signals from two or more signaling pathways and relay the signal onward along a single pathway.

Latent gene regulatory proteins are activated by receptors at the cell surface and migrate to the nucleus, where they stimulate gene transcription.

Mediators act as molecular go-betweens in signaling cascades. Second messengers are small, readily diffusible molecules that operate in signal transduction (calcium ions, cAMP, cGMP, ceramide, diacylglycerol, inositol-1,4,5-trisphosphate).

Messenger proteins carry the signal from one part of the cell to another. For example, messengers often carry signals from the cytosol to the nucleus.

Modulator proteins regulate the activity of other proteins. Calmodulin (Ca2+-regulated modulator protein, CaM) is a ubiquitous eukaryotic intracellular calcium receptor that regulates the biological activities of many cellular proteins and transmembrane ion transporters. The Ca2+•calmodulin complex binds target proteins, initiating various signaling cascades.

Relay proteins pass the message to the next signaling component in the chain without otherwise participating.

Scaffold proteins either hold protein kinases in a latent state close to their activating cell-surface receptors, or facilitate flow of activation from one kinase to the next kinase in a signaling cascade. The A kinase anchoring proteins (AKAPs) are prototypical anchor/scaffold proteins that organize the protein kinases and phosphatases that regulate serine/threonine phosphorylation.

Transducer proteins convert the signal from one form to another. Signaling enzymes that produce cyclic AMP, for example, both convert the received signal and amplify it (transducer and amplifier).

'Signaling' domains are found in intracellular proteins that are involved in signaling cascades:
● EF hand domains
● PDZ domains
● pleckstrin homology (PH) domain family
● SH2 domains

Cell-surface adhesion interactions and inflammatory responses employ specialized domains:
● cadherin repeats
● carbohydrate-recognition domain (CRD)
● caspase recruiting domains, CARD domains
● C-lectin domain (CRD)
● C-type-lectin-like domain (CTLD)
● death domain (DD), death effector domain (DED) binds adaptor protein FADD (Fas-Associated Death Domain)
● zinc finger DNA binding domains

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