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Guanine nucleotide exchange factor

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Title: Guanine nucleotide exchange factor  
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Guanine nucleotide exchange factor

GTP
GDP

Guanine nucleotide exchange factors (GEFs) activate monomeric GTPases by stimulating the release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP).[1] A variety of unrelated structural domains have been shown to exhibit guanine nucleotide exchange activity. Some GEFs can activate multiple GTPases while others are specific to a single GTPase.

Contents

  • Function 1
  • Mechanism 2
  • Structure and Specificity 3
    • CDC25 Domain 3.1
    • DH and PH Domains 3.2
    • DHR2 Domain 3.3
    • Sec7 Domain 3.4
  • Regulation 4
  • GEFs and Cancer 5
  • Examples of GEFs 6
  • See also 7
  • References 8
  • External links 9

Function

Schematic of GEF activation of a GTPase

Guanine Nucleotide Exchange Factors (GEFs) are proteins involved in the activation of

  • MBInfo - Glossary Terms: GAPs, GEFs, and GDIs

External links

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return p

end

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function p._hatnote(s, options) checkType('_hatnote', 1, s, 'string') checkType('_hatnote', 2, options, 'table', true) local classes = {'hatnote'} local extraclasses = options.extraclasses local selfref = options.selfref if type(extraclasses) == 'string' then classes[#classes + 1] = extraclasses end if selfref then classes[#classes + 1] = 'selfref' end return string.format( '

function p.hatnote(frame) local args = getArgs(frame) local s = args[1] local options = {} if not s then return p.makeWikitextError( 'no text specified', 'Template:Hatnote#Errors', args.category ) end options.extraclasses = args.extraclasses options.selfref = args.selfref return p._hatnote(s, options) end


-- Hatnote -- -- Produces standard hatnote text. Implements the template.


function p._formatLink(link, display) -- Find whether we need to use the colon trick or not. We need to use the -- colon trick for categories and files, as otherwise category links -- categorise the page and file links display the file. checkType('_formatLink', 1, link, 'string') checkType('_formatLink', 2, display, 'string', true) link = removeInitialColon(link) local namespace = p.findNamespaceId(link, false) local colon if namespace == 6 or namespace == 14 then colon = ':' else colon = end -- Find whether a faux display value has been added with the | magic -- word. if not display then local prePipe, postPipe = link:match('^(.-)|(.*)$') link = prePipe or link display = postPipe end -- Find the display value. if not display then local page, section = link:match('^(.-)#(.*)$') if page then display = page .. ' § ' .. section end end -- Assemble the link. if display then return string.format('%s', colon, link, display) else return string.format('%s%s', colon, link) end end

function p.formatLink(frame) local args = getArgs(frame) local link = args[1] local display = args[2] if not link then return p.makeWikitextError( 'no link specified', 'Template:Format hatnote link#Errors', args.category ) end return p._formatLink(link, display) end


-- Format link -- -- Makes a wikilink from the given link and display values. Links are escaped -- with colons if necessary, and links to sections are detected and displayed -- with " § " as a separator rather than the standard MediaWiki "#". Used in -- the template.


function p.makeWikitextError(msg, helpLink, addTrackingCategory) -- Formats an error message to be returned to wikitext. If -- addTrackingCategory is not false after being returned from -- Module:Yesno, and if we are not on a talk page, a tracking category -- is added. checkType('makeWikitextError', 1, msg, 'string') checkType('makeWikitextError', 2, helpLink, 'string', true) yesno = require('Module:Yesno') local title = mw.title.getCurrentTitle() -- Make the help link text. local helpText if helpLink then helpText = ' (help)' else helpText = end -- Make the category text. local category if not title.isTalkPage and yesno(addTrackingCategory) ~= false then category = 'Hatnote templates with errors' category = string.format( '%s:%s', mw.site.namespaces[14].name, category ) else category = end return string.format( '%s', msg, helpText, category ) end

function p.formatPageTables(...) -- Takes a list of page/display tables and returns it as a list of -- formatted links. Nil values are not allowed. local pages = {...} local links = {} for i, t in ipairs(pages) do checkType('formatPageTables', i, t, 'table') local link = t[1] local display = t[2] links[i] = p._formatLink(link, display) end return links end

function p.formatPages(...) -- Formats a list of pages using formatLink and returns it as an array. Nil -- values are not allowed. local pages = {...} local ret = {} for i, page in ipairs(pages) do ret[i] = p._formatLink(page) end return ret end

function p.findNamespaceId(link, removeColon) -- Finds the namespace id (namespace number) of a link or a pagename. This -- function will not work if the link is enclosed in double brackets. Colons -- are trimmed from the start of the link by default. To skip colon -- trimming, set the removeColon parameter to true. checkType('findNamespaceId', 1, link, 'string') checkType('findNamespaceId', 2, removeColon, 'boolean', true) if removeColon ~= false then link = removeInitialColon(link) end local namespace = link:match('^(.-):') if namespace then local nsTable = mw.site.namespaces[namespace] if nsTable then return nsTable.id end end return 0 end

local function removeInitialColon(s) -- Removes the initial colon from a string, if present. return s:match('^:?(.*)') end

local function getArgs(frame) -- Fetches the arguments from the parent frame. Whitespace is trimmed and -- blanks are removed. mArguments = require('Module:Arguments') return mArguments.getArgs(frame, {parentOnly = true}) end


-- Helper functions


local p = {}

local libraryUtil = require('libraryUtil') local checkType = libraryUtil.checkType local mArguments -- lazily initialise Module:Arguments local yesno -- lazily initialise Module:Yesno


return p-------------------------------------------------------------------------------- -- Module:Hatnote -- -- -- -- This module produces hatnote links and links to related articles. It -- -- implements the and meta-templates and includes -- -- helper functions for other Lua hatnote modules. --

end

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function p._hatnote(s, options) checkType('_hatnote', 1, s, 'string') checkType('_hatnote', 2, options, 'table', true) local classes = {'hatnote'} local extraclasses = options.extraclasses local selfref = options.selfref if type(extraclasses) == 'string' then classes[#classes + 1] = extraclasses end if selfref then classes[#classes + 1] = 'selfref' end return string.format( '

function p.hatnote(frame) local args = getArgs(frame) local s = args[1] local options = {} if not s then return p.makeWikitextError( 'no text specified', 'Template:Hatnote#Errors', args.category ) end options.extraclasses = args.extraclasses options.selfref = args.selfref return p._hatnote(s, options) end


-- Hatnote -- -- Produces standard hatnote text. Implements the template.


function p._formatLink(link, display) -- Find whether we need to use the colon trick or not. We need to use the -- colon trick for categories and files, as otherwise category links -- categorise the page and file links display the file. checkType('_formatLink', 1, link, 'string') checkType('_formatLink', 2, display, 'string', true) link = removeInitialColon(link) local namespace = p.findNamespaceId(link, false) local colon if namespace == 6 or namespace == 14 then colon = ':' else colon = end -- Find whether a faux display value has been added with the | magic -- word. if not display then local prePipe, postPipe = link:match('^(.-)|(.*)$') link = prePipe or link display = postPipe end -- Find the display value. if not display then local page, section = link:match('^(.-)#(.*)$') if page then display = page .. ' § ' .. section end end -- Assemble the link. if display then return string.format('%s', colon, link, display) else return string.format('%s%s', colon, link) end end

function p.formatLink(frame) local args = getArgs(frame) local link = args[1] local display = args[2] if not link then return p.makeWikitextError( 'no link specified', 'Template:Format hatnote link#Errors', args.category ) end return p._formatLink(link, display) end


-- Format link -- -- Makes a wikilink from the given link and display values. Links are escaped -- with colons if necessary, and links to sections are detected and displayed -- with " § " as a separator rather than the standard MediaWiki "#". Used in -- the template.


function p.makeWikitextError(msg, helpLink, addTrackingCategory) -- Formats an error message to be returned to wikitext. If -- addTrackingCategory is not false after being returned from -- Module:Yesno, and if we are not on a talk page, a tracking category -- is added. checkType('makeWikitextError', 1, msg, 'string') checkType('makeWikitextError', 2, helpLink, 'string', true) yesno = require('Module:Yesno') local title = mw.title.getCurrentTitle() -- Make the help link text. local helpText if helpLink then helpText = ' (help)' else helpText = end -- Make the category text. local category if not title.isTalkPage and yesno(addTrackingCategory) ~= false then category = 'Hatnote templates with errors' category = string.format( '%s:%s', mw.site.namespaces[14].name, category ) else category = end return string.format( '%s', msg, helpText, category ) end

function p.formatPageTables(...) -- Takes a list of page/display tables and returns it as a list of -- formatted links. Nil values are not allowed. local pages = {...} local links = {} for i, t in ipairs(pages) do checkType('formatPageTables', i, t, 'table') local link = t[1] local display = t[2] links[i] = p._formatLink(link, display) end return links end

function p.formatPages(...) -- Formats a list of pages using formatLink and returns it as an array. Nil -- values are not allowed. local pages = {...} local ret = {} for i, page in ipairs(pages) do ret[i] = p._formatLink(page) end return ret end

function p.findNamespaceId(link, removeColon) -- Finds the namespace id (namespace number) of a link or a pagename. This -- function will not work if the link is enclosed in double brackets. Colons -- are trimmed from the start of the link by default. To skip colon -- trimming, set the removeColon parameter to true. checkType('findNamespaceId', 1, link, 'string') checkType('findNamespaceId', 2, removeColon, 'boolean', true) if removeColon ~= false then link = removeInitialColon(link) end local namespace = link:match('^(.-):') if namespace then local nsTable = mw.site.namespaces[namespace] if nsTable then return nsTable.id end end return 0 end

local function removeInitialColon(s) -- Removes the initial colon from a string, if present. return s:match('^:?(.*)') end

local function getArgs(frame) -- Fetches the arguments from the parent frame. Whitespace is trimmed and -- blanks are removed. mArguments = require('Module:Arguments') return mArguments.getArgs(frame, {parentOnly = true}) end


-- Helper functions


local p = {}

local libraryUtil = require('libraryUtil') local checkType = libraryUtil.checkType local mArguments -- lazily initialise Module:Arguments local yesno -- lazily initialise Module:Yesno


-- Module:Hatnote -- -- -- -- This module produces hatnote links and links to related articles. It -- -- implements the and meta-templates and includes -- -- helper functions for other Lua hatnote modules. --


References


See also

  • Son of sevenless (SOS1) is an important GEF in the cell growth-regulatory MAPK/ERK pathway. SOS1 binds GRB2 at the plasma membrane after EGF receptor activation. SOS1 activates the small G protein Ras.[16]
  • eIF-2b is a eukaryotic initiation factor necessary to initiate protein translation. eIF-2b regenerates the GTP-bound form of eIF-2 for an additional cycle in protein synthesis initiation, i.e., its binding to the Met-t-RNA.[18]
  • G protein-coupled receptors are trans-membrane receptors that act as GEFs for their cognate G proteins upon binding of a ligand. Ligand binding induces a conformational change that allows the GPCR to activate an associated GTPase.[2]
  • RCC1 is the guanine nucleotide exchange factor for Ran GTPase. It localizes to the nucleus and catalyzes the activation of Ran to allow nuclear export of proteins.[8]
  • Ras-GRF1
  • Kalirin

Examples of GEFs

GEFs are potential target for cancer therapy due to their role in many signaling pathways, particularly cell proliferation. For example, many cancers are caused by mutations in the MAPK/ERK pathway that lead to uncontrolled growth. The GEF SOS1 activates Ras, whose target is the kinase Raf. Raf is a proto-oncogene because mutations in this protein have been found in many cancers.[6][12] The Rho GTPase Vav1, which can be activated by the GEF receptor, has been shown to promote tumor proliferation in pancreatic cancer.[17] GEFs represent possible therapeutic targets as they can potentially play a role in regulating these pathways through their activation of GTPases.

GEFs and Cancer

Crosstalk has also been shown between GEFs and multiple GTPase signaling pathways. For example, SOS contains a Dbl homology domain in addition to its CDC25 catalytic domain. SOS can act as a GEF to activate Rac1, a RhoGTPase, in addition to its role as a GEF for Ras. SOS is therefore a link between the Ras-Family and Rho-Family GTPase signaling pathways.[13]

GEFs are often recruited by adaptor proteins in response to upstream signals. GEFs are multi-domain proteins and interact with other proteins inside the cell through these domains.[12] Adaptor proteins can modulate GEF activity by interacting with other domains besides the catalytic domain. For example, SOS1, the Ras GEF in the MAPK/ERK pathway, is recruited by the adaptor protein GRB2 in response to EGF receptor activation. The binding of SOS1 to GBR2 localizes it to the plasma membrane, where it can activate the membrane bound Ras.[16] Other GEFs, such as the Rho GEF Vav1, are activated upon phosphorylation in response to upstream signals.[17] Secondary messengers such as cAMP and calcium can also play a role in GEF activation.[3]

Regulation

The Sec7 domain is responsible for the GEF catalytic activity in ARF GTPases. ARF proteins function in vesicle trafficking. Though ARF GEFs are divergent in their overall sequences, they contain a conserved Sec 7 domain. This 200 amino acid region is homologous to the yeast Sec7p protein.[15]

Sec7 Domain

The DHR2 domain is the catalytic domain of the DOCK family of Rho GEFs. The DOCK family is a separate subset of GEFs from the Dbl family and bears no structural or sequence relation to the DH domain. There are 11 identified DOCK family members divided into subfamilies based on their activation of Rac and Cdc42. DOCK family members are involved in cell migration, morphogenesis and phagocytosis. The DHR2 domain is approximately 400 amino acids. These proteins also contain a second conserved domain, DHR1, which is approximately 250 amino acids. The DHR1 domain been shown to be involved in the membrane localization of some GEFs.[14]

DHR2 Domain

The Dbl homology and Pleckstrin homology domains are present in all Dbl family members, which act as GEFs for Rho GTPases.[11] The DH domain, also known as the RhoGEF domain, is responsible for GEF catalytic activity. The PH domain is involved in intracellular targeting of the DH domain. The PH domain is generally thought to modulate membrane binding through interactions with phospholipids, but its function has been shown to vary in different proteins.[12][13] This PH domain is also present in other proteins beyond RhoGEFs. Together, these two domains constitute the minimum structural unit necessary for the activity of Dbl family proteins. The PH domain is located immediately adjacent to the C terminus of the DH domain. There are approximately 70 identified Dbl RhoGEFs in humans. Many of the mammalian Dbl family proteins are cell-type specific.[13]

DH and PH Domains

The CDC25 homology domain, also called the RasGEF domain, is the catalytic domain of many Ras GEFs, which activate Ras GTPases. The CDC25 domain comprises approximately 500 amino acids and was first identified in the CDC25 protein in budding yeast Saccharomyces cerevisiae.[10]

CDC25 Domain

Some GEFs are specific to a single GTPase while others have multiple GTPase substrates. While different subfamilies of Ras superfamily GTPases have a conserved GTP binding domain, this is not the case for GEFs. Different families of GEFs correspond to different Ras subfamilies. The functional domains of these GEF families are not structurally related and do not share sequence homology. These GEF domains appear to be evolutionarily unrelated despite similar function and substrates.[7]

Structure and Specificity

The mechanism of GTPase activation varies among different GEFs. However, there are some similarities in how different GEFs alter the conformation of the G protein nucleotide-binding site. GTPases contain two loops called switch 1 and switch 2 that are situated on either side of the bound nucleotide. These regions and the phosphate-binding loop of the GTPase interact with the phosphates of the nucleotide and a coordinating magnesium ion to maintain high affinity binding of the nucleotide. GEF binding induces conformational changes in the P loop and switch regions of the GTPase while the rest of the structure is largely unchanged. The binding of the GEF sterically hinders the magnesium-binding site and interferes with the phosphate-binding region, while the base-binding region remains accessible. When the GEF binds the GTPase, the phosphate groups are released first and the GEF is displaced upon binding of the entering GTP molecule. Though this general scheme is common among GEFs, the specific interactions between the regions of the GTPase and GEF vary among individual proteins.[9]

Mechanism

The localization of GEFs can determine where in the cell a particular GTPase will be active. For example, the Ran GEF, RCC1, is present in the nucleus while the Ran GAP is present in the cytosol, modulating nuclear import and export of proteins.[8] RCC1 converts RanGDP to RanGTP in the nucleus, activating Ran for the export of proteins. When the Ran GAP catalyzes conversion of RanGTP to RanGDP in the cytosol, the protein cargo is released.

GDP dissociates from inactive GTPases very slowly.[3] The binding of GEFs to their GTPase substrates catalyzes the dissociation of GDP, allowing a GTP molecule to bind in its place. GEFs function to promote the dissociation of GDP. After GDP has disassociated from the GTPase, GTP generally binds in its place, as the cytosolic ratio of GTP is much higher than GDP at 10:1.[4] The binding of GTP to the GTPase results in the release of the GEF, which can then activate a new GTPase.[5][6] Thus, GEFs both destabilize the GTPase interaction with GDP and stabilize the nucleotide-free GTPase until a GTP molecule binds to it.[7] GAPs act antagonistically to inactivate GTPases by increasing their intrinsic rate of GTP hydrolysis. GDP remains bound to the inactive GTPase until a GEF binds and stimulates its release.[3]

[3] (GAPs).GTPase activating proteins GTPases are active when bound to GTP and inactive when bound to GDP, allowing their activity to be regulated by GEFs and the opposing [2]

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