Scaffold protein

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Function of scaffold proteins Scaffold Function.jpg
Function of scaffold proteins

In biology, scaffold proteins are crucial regulators of many key signalling pathways. Although scaffolds are not strictly defined in function, they are known to interact and/or bind with multiple members of a signalling pathway, tethering them into complexes. In such pathways, they regulate signal transduction and help localize pathway components (organized in complexes) to specific areas of the cell such as the plasma membrane, the cytoplasm, the nucleus, the Golgi, endosomes, and the mitochondria.

Contents

History

The first signaling scaffold protein discovered was the Ste5 protein from the yeast Saccharomyces cerevisiae . Three distinct domains of Ste5 were shown to associate with the protein kinases Ste11, Ste7, and Fus3 to form a multikinase complex. [2]

Function

Scaffold proteins act in at least four ways: tethering signaling components, localizing these components to specific areas of the cell, regulating signal transduction by coordinating positive and negative feedback signals, and insulating correct signaling proteins from competing proteins. [1]

Tethering signaling components

This particular function is considered a scaffold's most basic function. Scaffolds assemble signaling components of a cascade into complexes. This assembly may be able to enhance signaling specificity by preventing unnecessary interactions between signaling proteins, and enhance signaling efficiency by increasing the proximity and effective concentration of components in the scaffold complex. A common example of how scaffolds enhance specificity is a scaffold that binds a protein kinase and its substrate, thereby ensuring specific kinase phosphorylation. Additionally, some signaling proteins require multiple interactions for activation and scaffold tethering may be able to convert these interactions into one interaction that results in multiple modifications. [3] [4] Scaffolds may also be catalytic as interaction with signaling proteins may result in allosteric changes of these signaling components. [5] Such changes may be able to enhance or inhibit the activation of these signaling proteins. An example is the Ste5 scaffold in the mitogen-activated protein kinase (MAPK) pathway. Ste5 has been proposed to direct mating signaling through the Fus3 MAPK by catalytically unlocking this particular kinase for activation by its MAPKK Ste7. [6]

Localization of signaling components in the cell

Scaffolds localize the signaling reaction to a specific area in the cell, a process that could be important for the local production of signaling intermediates. A particular example of this process is the scaffold, A-kinase anchor proteins (AKAPs), which target cyclic AMP-dependent protein kinase (PKA) to various sites in the cell. [7] This localization is able to locally regulate PKA and results in the local phosphorylation by PKA of its substrates.

Coordinating positive and negative feedback

Many hypotheses about how scaffolds coordinate positive and negative feedback come from engineered scaffolds and mathematical modeling. In three-kinase signaling cascades, scaffolds bind all three kinases, enhancing kinase specificity and restricting signal amplification by limiting kinase phosphorylation to only one downstream target. [3] [8] [9] These abilities may be related to stability of the interaction between the scaffold and the kinases, the basal phosphatase activity in the cell, scaffold location, and expression levels of the signaling components. [3] [8]

Insulating correct signaling proteins from inactivation

Signaling pathways are often inactivated by enzymes that reverse the activation state and/or induce the degradation of signaling components. Scaffolds have been proposed to protect activated signaling molecules from inactivation and/or degradation. Mathematical modeling has shown that kinases in a cascade without scaffolds have a higher probability of being dephosphorylated by phosphatases before they are even able to phosphorylate downstream targets. [8] Furthermore, scaffolds have been shown to insulate kinases from substrate- and ATP-competitive inhibitors. [10]

Scaffold protein summary

Scaffold ProteinsPathwayPotential FunctionsDescription
KSR MAPK Assembly and localization of the RAS-ERK pathwayOne of the best studied signaling pathways in biology is the RAS-ERK pathway in which the RAS G-protein activates the MAPKKK RAF, which activates the MAPKK MEK1 (MAPK/ERK kinase 1), which then activates the MAPK ERK. Several scaffold proteins have been identified to be involved in this pathway and other similar MAPK pathways. One such scaffold protein is KSR, which is the most probable equivalent of the well-studied yeast MAPK scaffold protein Ste5. [11] It is a positive regulator of the pathway and binds many proteins in the pathway, including all three kinases in the cascade. [6] KSR has been shown to be localized to the plasma membrane during cell activation, thereby playing a role in assembling the components of the ERK pathway and in localizing activated ERK to the plasma membrane. [12]
MEKK1 MAPKAssembly and localization of the death receptor signalosomeOther scaffold proteins include B-cell lymphoma 10 (BCL-10) and MEK kinase 1 (MEKK1), which have roles in the JUN N-terminal kinase (JNK) pathway.
BCL-10 MAPKAssembly and specificity of JNK
AKAP PKA PathwaysCoordination of phosphorylation by PKA onto downstream targetsThis family of proteins is only structurally related in their ability to bind the regulatory subunit of PKA but can otherwise bind a very diverse set of enzymes and substrates
AHNAK-1 Calcium signaling Assembly and localization of calcium channelsCalcium signaling is essential for the proper function of immune cells. Recent studies have shown that the scaffold protein, AHNAK1, is important for efficient calcium signaling and NFAT activation in T cells through its ability to properly localize calcium channels at the plasma membrane [14]. In non-immune cells, AHNAK1 has also been shown to bind calcium channels with phospholipase Cγ (PLC-γ) and PKC. [1] Calcium binding proteins often quench much of the entering calcium, so linking these calcium effectors may be especially important when signals are induced by a weak calcium influx.
HOMER Calcium signalingInhibition of NFAT activationAnother example of a scaffold protein that modulates calcium signaling is proteins of the HOMER family. The HOMER proteins have been shown to compete with calcineurin to bind to the N terminus of NFAT in activated T cells. [13] Through this competition, the HOMER proteins are able to reduce NFAT activation, which also reduces the production of the IL-2 cytokine. [13] In contrast, HOMER proteins have also been shown to positively regulate calcium signaling in neurons by linking the glutamate receptor with triphosphate receptors in the endoplasmic reticulum. [14]
Pellino Innate Immune SignalingAssembly of the TLR signalosomeEvidence exists that Pellino proteins function as scaffold proteins in the important innate immune signaling pathway, the Toll-like receptor (TLR) pathway. Much Pellino function is speculation; however, Pellino proteins can associate with IRAK1, TRAF6, and TAK1 following IL-1R activation, indicating that they may assemble and localize components of the TLR pathway near its receptor. [15] [16]
NLRP Innate Immune SignalingAssembly of the inflammasomeThe NLR family is a highly conserved and large family of receptors involved in innate immunity. The NLRP (NLR family, pyrine domain-containing) family of receptors function as scaffolds by assembling the inflammasome, a complex that leads to the secretion of pro-inflammatory cytokines such as IL-18 and IL-1β. [17]
DLG1 T-cell receptor signalingAssembly and localization of TCR signaling molecules, activation of p38DLG1 is highly conserved in immune cells and is important for T-cell activation in the periphery. It is recruited to the immunological synapse and links the ζ-chain of the T-cell receptor (TCR) to CBL, WASP, p38, LCK, VAV1, and ZAP70. [18] [19] [20] [21] This data suggests that DLG1 plays a role in linking TCR signaling machinery with cytoskeleton regulators and also suggests a role in alternatively activating the p38 pathway. However, it is unclear to whether DLG1 positively or negatively regulates T-cell activation.
Spinophilin Dendritic cell signalingAssembly of DC immunological-synapse proteinsSpinophilin is involved in dendritic cell function specifically in the formation of immunological synapses. Spinophilin is recruited to the synapse following dendritic cell contact with a T cell. This recruitment seems to be important because without spinophilin, dendritic cells cannot activate T cells in vitro or in vivo. [22] How spinophilin facilitates antigen presentation in this case is still unknown though it is possible that spinophilin regulates the duration of cell contact in the synapse or regulates the recycling of co-stimulatory molecules in the cell like MHC molecules. [1]
Plant FLU regulatory protein [23] Coordination of negative feedback during protochlorophyllide biosynthesis.Assembly and localization of the pathway that turns the synthesis of highly toxic protochlorophyllide, a precursor of chlorophyll.Synthesis of protochlorophyllide must be strictly regulated as its conversion into chlorophyll requires light. FLU regulatory protein is located in thylakoid membrane and only contains several protein-protein interaction sites without catalytic activity. Mutants lacking this protein overaccumulate protochlorophyllide in the darkness. The interaction partners are unknown. The protein underwent simplification during evolution.

Huntingtin protein

Huntingtin protein co-localizes with ATM repair protein at sites of DNA damage. [24] Huntingtin is a scaffolding protein in the ATM oxidative DNA damage response complex. [24] Huntington’s disease patients with aberrant huntingtin protein are deficient in repair of oxidative DNA damage. Oxidative DNA damage appears to underlie Huntington’s disease pathogenesis. [25] Huntington’s disease is likely caused by the dysfunction of mutant huntingtin scaffold protein in DNA repair leading to increased oxidative DNA damage in metabolically active cells. [24]

DNA repair

SPIDR (scaffold protein involved in DNA repair) regulates the stability or assembly of RAD51 and DMC1 on single-stranded DNA. [26] RAD51 and DMC1 are recombinases that act during mammalian meiosis to mediate strand exchange during the repair of DNA double-strand breaks by homologous recombination. [26]

Other usage of the term Scaffold Protein

On some other instances in biology (not necessarily about cell signaling), the term "Scaffold protein" is used in a broader sense, where a protein holds several things together for any purpose.

In chromosome folding
Chromosome scaffold has important role to hold the chromatin into compact chromosome. Chromosome scaffold is made of proteins including condensin, topoisomerase IIα and kinesin family member 4 (KIF4) [27] Chromosome scaffold constituent proteins are also called scaffold protein.
In enzymatic reaction
Large multifunctional enzymes that performs a series or chain of reaction in a common pathway, sometimes called scaffold proteins. [28] such as Pyruvate dehydrogenase.
In molecule shape formation
An enzyme or structural protein that holds several molecules together to hold them in proper spatial arrangement, such as Iron sulphur cluster scaffold proteins. [29] [30]
Structural scaffold
In cytoskeleton and ECM, the molecules provide mechanical scaffold. Such as type 4 collagen [31]

Related Research Articles

A mitogen-activated protein kinase is a type of protein kinase that is specific to the amino acids serine and threonine. MAPKs are involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflammatory cytokines. They regulate cell functions including proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis.

A biochemical cascade, also known as a signaling cascade or signaling pathway, is a series of chemical reactions that occur within a biological cell when initiated by a stimulus. This stimulus, known as a first messenger, acts on a receptor that is transduced to the cell interior through second messengers which amplify the signal and transfer it to effector molecules, causing the cell to respond to the initial stimulus. Most biochemical cascades are series of events, in which one event triggers the next, in a linear fashion. At each step of the signaling cascade, various controlling factors are involved to regulate cellular actions, in order to respond effectively to cues about their changing internal and external environments.

Biological crosstalk refers to instances in which one or more components of one signal transduction pathway affects another. This can be achieved through a number of ways with the most common form being crosstalk between proteins of signaling cascades. In these signal transduction pathways, there are often shared components that can interact with either pathway. A more complex instance of crosstalk can be observed with transmembrane crosstalk between the extracellular matrix (ECM) and the cytoskeleton.

Mitogen Activated Protein (MAP) kinase kinase kinase is a serine/threonine-specific protein kinase which acts upon MAP kinase kinase. Subsequently, MAP kinase kinase activates MAP kinase. Several types of MAPKKK can exist but are mainly characterized by the MAP kinases they activate. MAPKKKs are stimulated by a large range of stimuli, primarily environmental and intracellular stressors. MAPKKK is responsible for various cell functions such as cell proliferation, cell differentiation, and apoptosis. The duration and intensity of signals determine which pathway ensues. Additionally, the use of protein scaffolds helps to place the MAPKKK in close proximity with its substrate to allow for a reaction. Lastly, because MAPKKK is involved in a series of several pathways, it has been used as a therapeutic target for cancer, amyloidosis, and neurodegenerative diseases. In humans, there are at least 19 genes which encode MAP kinase kinase kinases:

In molecular biology, extracellular signal-regulated kinases (ERKs) or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells. Many different stimuli, including growth factors, cytokines, virus infection, ligands for heterotrimeric G protein-coupled receptors, transforming agents, and carcinogens, activate the ERK pathway.

<span class="mw-page-title-main">Mitogen-activated protein kinase 9</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase 9 is an enzyme that in humans is encoded by the MAPK9 gene.

<span class="mw-page-title-main">ASK1</span> Protein-coding gene in the species Homo sapiens

Apoptosis signal-regulating kinase 1 (ASK1) also known as mitogen-activated protein kinase 5 (MAP3K5) is a member of MAP kinase family and as such a part of mitogen-activated protein kinase pathway. It activates c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases in a Raf-independent fashion in response to an array of stresses such as oxidative stress, endoplasmic reticulum stress and calcium influx. ASK1 has been found to be involved in cancer, diabetes, rheumatoid arthritis, cardiovascular and neurodegenerative diseases.

<span class="mw-page-title-main">MAPK14</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase 14, also called p38-α, is an enzyme that in humans is encoded by the MAPK14 gene.

<span class="mw-page-title-main">ELK1</span> Protein-coding gene in humans

ETS Like-1 protein Elk-1 is a protein that in humans is encoded by the ELK1. Elk-1 functions as a transcription activator. It is classified as a ternary complex factor (TCF), a subclass of the ETS family, which is characterized by a common protein domain that regulates DNA binding to target sequences. Elk1 plays important roles in various contexts, including long-term memory formation, drug addiction, Alzheimer's disease, Down syndrome, breast cancer, and depression.

<span class="mw-page-title-main">MAP2K6</span> Protein-coding gene in the species Homo sapiens

Dual specificity mitogen-activated protein kinase kinase 6 also known as MAP kinase kinase 6 or MAPK/ERK kinase 6 is an enzyme that in humans is encoded by the MAP2K6 gene, on chromosome 17.

<span class="mw-page-title-main">MAP2K3</span> Protein-coding gene in the species Homo sapiens

Dual specificity mitogen-activated protein kinase kinase 3 is an enzyme that in humans is encoded by the MAP2K3 gene.

<span class="mw-page-title-main">RPS6KA1</span> Enzyme

Ribosomal protein S6 kinase alpha-1 is an enzyme that in humans is encoded by the RPS6KA1 gene.

<span class="mw-page-title-main">MAP3K1</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) is a signal transduction enzyme that in humans is encoded by the autosomal MAP3K1 gene.

<span class="mw-page-title-main">MAP2K7</span> Protein-coding gene in the species Homo sapiens

Dual specificity mitogen-activated protein kinase kinase 7, also known as MAP kinase kinase 7 or MKK7, is an enzyme that in humans is encoded by the MAP2K7 gene. This protein is a member of the mitogen-activated protein kinase kinase family. The MKK7 protein exists as six different isoforms with three possible N-termini and two possible C-termini.

<span class="mw-page-title-main">MAP3K10</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase kinase kinase 10 is an enzyme that in humans is encoded by the MAP3K10 gene.

<span class="mw-page-title-main">MAP2K1IP1</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase scaffold protein 1 is a scaffold protein that in humans is encoded by the MAPKSP1 gene.

<span class="mw-page-title-main">MAPK4</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase 4 is an enzyme that in humans is encoded by the MAPK4 gene.

<span class="mw-page-title-main">Hippo signaling pathway</span> Signaling pathway that controls organ size

The Hippo signaling pathway, also known as the Salvador-Warts-Hippo (SWH) pathway, is a signaling pathway that controls organ size in animals through the regulation of cell proliferation and apoptosis. The pathway takes its name from one of its key signaling components—the protein kinase Hippo (Hpo). Mutations in this gene lead to tissue overgrowth, or a "hippopotamus"-like phenotype.

<span class="mw-page-title-main">Ste5</span>

Ste5 is a MAPK scaffold protein involved in the mating of yeast. The active complex is formed by interactions with the MAPK Fus3, the MAPK kinase (MAPKK) Ste7, and the MAPKK kinase Ste11. After the induction of mating by an appropriate mating pheromone Ste5 and its associated proteins are recruited to the membrane.

The interleukin-1 receptor (IL-1R) associated kinase (IRAK) family plays a crucial role in the protective response to pathogens introduced into the human body by inducing acute inflammation followed by additional adaptive immune responses. IRAKs are essential components of the Interleukin-1 receptor signaling pathway and some Toll-like receptor signaling pathways. Toll-like receptors (TLRs) detect microorganisms by recognizing specific pathogen-associated molecular patterns (PAMPs) and IL-1R family members respond the interleukin-1 (IL-1) family cytokines. These receptors initiate an intracellular signaling cascade through adaptor proteins, primarily, MyD88. This is followed by the activation of IRAKs. TLRs and IL-1R members have a highly conserved amino acid sequence in their cytoplasmic domain called the Toll/Interleukin-1 (TIR) domain. The elicitation of different TLRs/IL-1Rs results in similar signaling cascades due to their homologous TIR motif leading to the activation of mitogen-activated protein kinases (MAPKs) and the IκB kinase (IKK) complex, which initiates a nuclear factor-κB (NF-κB) and AP-1-dependent transcriptional response of pro-inflammatory genes. Understanding the key players and their roles in the TLR/IL-1R pathway is important because the presence of mutations causing the abnormal regulation of Toll/IL-1R signaling leading to a variety of acute inflammatory and autoimmune diseases.

References

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