Main protein domains in STP

Main protein domains in STP MAIN PROTEIN DOMAINS INVOLVED IN STP

Table of contents :

ligand-binding domains (LBDs)

DNA-binding domains (DBDs)

chromatin-binding domains

pY motifs

pY motifs-binding domains

pS/T motifs-binding domains

Pro-rich motifs-binding domains

phospholipid-binding domains

apoptotic proteins domains

proteolysis domains

dimerization domains

domains with undefined functions

miscellaneous domains

ligand-binding domains (LBDs)

CC WSXWS domains : in type I cytokine receptors (IL-2R , IL-4R , IL-5R , IL-6R , IL-7R , IL-9R , IL-11R , IL-13R , IL-15R , GM-CSFR , G-CSFR )
Ig domain (immunoglobulin : antiparallel b-folds with a disulfide bond-closed loop between B and F folds ; 60÷75 amino acids ; a.k.a. D in KIRs) : in IgSF (BcR , IL-1R , IL-18R ...). Each Ig domain consists of 7 antiparallel beta strands, arranged in 2 sheets of 4 and 3 strands respectively. The 3 sheets are covalently linked with a single disulphide bond (shown here as a yellow rod). This cartoon representation is colored with RasMol's group color scheme, which makes the N/amino terminus blue, and the C/carboxy terminus red, with a spectral color sequence between these ends.

homology regions : regions of immunoglobulin heavy and light chains containing about 110 amino acid residues and forming compact globular domains stabilized by one intrachain disulfide bond; they have a high degree of sequence homology and similar 3D structure. Each variable region (V_H and V_L) of heavy and light chains and the light chain constant region (C_L) are coextensive with a single homology region. Heavy chain constant regions are composed of 3 (in g, d, and a chains) or 4 (in m and e chains) homology regions, C_H1, C_H2, C_H3, and C_H4, and a hinge region separating C_H1 and C_H2.

Leu-rich repeat (LLR) has a consensus sequence motif (L(X)₂LXL(X)₂NXL(X)₂L(X)₂L(X)₂)). It is usually extracellular (e.g. in TLRs ) and is separated from the transmembrane region by a LRR-carboxy-terminal domain, which is characterized by the consensus motf CXC(X₂₃)C(X₁₇)C.
carbohydrate recognition domain (CRD) allows Ca²⁺ and carbohydrate binding. E.g. in lectins.

DNA-binding domains (DBDs)

zinc fingers (ZnF) are the most common DNA-binding motif, representing 1-2% of the human genome (about 700 human genes). Arabidopsis thaliana has about 85 zinc-finger genes. But, not all zinc-containing, DNA-binding proteins are true zinc fingers : only C₂H₂(cysteine₂-histidine₂) zinc proteins are "true" zinc fingers

Chromatin-binding domains

Bromo domains (left-handed up-and-down 4 helix bundle with a left handed twist) bind peptides containing acetylated Lys residues). E.g. in p/CAF (p300/CBP associated factor), peregrin, tafli-250, Snf 2, gcn5.
CD (Chromo domains, N-terminal 3-stranded anti-parallel b-sheet which folds against a N-terminal a-helix) bind chromatin. E.g. in N-terminus of HP1, Polycomb, RBP1.
CSD (C-terminal shadow Chromo domains, 3-stranded antiparallel b-sheet followed by 2 a-helices). E.g. in C-terminus of Swi-5, HP-1, Ku70, Su(var)3-7.

pY motifs

ITAM (immunoreceptor Tyr-based activation motif) or ARAM (Ag recognition activation motif) (Y-X-X-L-(X)_6-8-Y-X-X-L^ref) binds to SH2 domain. E.g. inCD247/x chain, FceRI g chain, DAP12. FcgR ITAM sequences in the FcR associated g-chain abide by this structure. However, the cytoplasmic domain of FcgRIIa contains an ITAM-like domain. This ITAM-like domain contains the 2 YxxL motifs but a spacer sequence containing 12 amino acids instead of the usual 7^ref. ITAM tyrosine residues have been shown to be crucial for mediating the phagocytic response. When either of the ITAM tyrosines are mutated to phenylalanine, phagocytosis is inhibited by ~70–80%. However, if both tyrosine residues are mutated phagocytosis is abolished^{ref1,
ref2,
ref3}. It has been proposed that ITAM tyrosines are phosphorylated by Src family kinases after crosslinking. Several members of the Src family have been shown to associate with specific FcgR. However, which Src kinase is responsible for phosphorylation of a specific FcgR is not established. Studies have been somewhat inconclusive in elucidating which kinase is responsible for phagocytic signaling through each FcgR. An example of these observations can be found in knockout experiments where phagocytosis is not abolished in Hck, Lyn, or Fgr single knockouts^ref. In addition, in triple knockout mice, phagocytosis by macrophages and neutrophils is still partially intact, suggesting other kinases may play a redundant role in phagocytosis^ref. Phosphorylation of ITAM tyrosines creates Src homology 2 (SH2)-binding sites required for signal transduction involving other members of the tyrosine kinase family^{ref1,
ref2,
ref3}. Most importantly, Syk tyrosine kinase, which contains 2 SH2-binding sites, is recruited to phosphorylated ITAM residues. FcgR phagocytosis is dependent upon Syk signaling, and has been observed to be enhanced upon the overexpression of Syk in model systems^ref. In addition, when Syk kinase expression is inhibited with antisense oligonucleotides both in vitro and in vivo, phagocytosis and inflammation are abolished^ref1,
ref2. SH2-containing proteins are important in signaling complexes. For example, recent studies have emphasized the role of adaptor proteins in phagocytic signaling. Adaptor molecules such as SLP-76, LAT, Cbl and others have the ability to recruit SH2-containing proteins to signaling complexes, notably in lipid rafts. These adaptor proteins play a significant role in recruiting such secondary signaling molecules as phospholipase C (PLC), Grb2, Shc and others. The ability for adaptor molecules to recruit proteins to the site of signal propagation by Fc receptors is important for efficiently triggering the downstream signaling leading to target internalization and mediator release.
ITIM (immunoreceptor Tyr-based inhibition motif) ([I/V]-X-Y-X-X-L) binds to SH2 domain in SHP1 and SHP2 recruiting them to the signaling complex. E.g. in KIR family, FcgRs,... Therefore, the presence of ITIM-bearing receptors imposes a negative effect. As such, the presence of FcgRIIB, an ITIM-bearing receptor, inhibits phagocytic signaling mediated by activating FcgRs^ref.
pY-X-N-M motifs bind to SH2 domain in PI(3)K. E.g. in DAP10.

pY motifs-binding domains

SH2 (Src-homology 2) domains (central anti-parallel b-sheet surrounded by 2 a-helices) bind specific pY-containing peptide motifs (specificity is conferred by a variable pocket that binds 3-6 residues C-terminal to the pY). E.g. in p60^c-Src, SAP, Btk, Grb2, Shc, STATs, Tensin, Rap1-GAP I/II, p190^{Rho/Rac GAP}, SHP-1/2, p85^PI(3)K, Nck1, Nck2, PK-C l/i, PL-Cg, SOCS-1/2/3, SSI-1, CIS, JAB, SEMS, c-Abl, Jip1, Bcr, Vav.
PTB (phosphotyrosine-binding) domains (2 orthogonal b-sheets and connecting loops) bind Asn-Pro-Xaa-(p)Tyr motifs. E.g. in Shc, IRS-1, X11, Dab, Fe65, Numb.

pS/T motifs-binding domains

FHA (Forkhead associated) domains (11-stranded b-sandwich that has a short a-helix inserted between b-strands 2 and 3 and an a-helical region at the extreme C-terminus). E.g. in AF-6, NBS/Nibrin, Rad53, IL EBF-2, KAPP.
14-3-3 domains (9 parallel a-helices). E.g. in 14-3-3a/x, Cdc25, Bad, c-Raf, PKC, MEKK1/2/3.

Pro-rich motifs-binding domains

SH3 (Src-homology 3) domains (5 antiparallel b-strands packed to form 2 perpendicular b-sheets) bind to Pro-rich peptides that form a left-handed polyPro type II helix. E.g. in STATs , Nck1, Nck2, p60^c-Src, Grb2, Shc, Rap1-GAP I/II, p190^Rho/Rac
GAP, p85^PI(3)K, c-Abl, Jip1, C3G, Vav.

conventional (PXXP binding) SH3 domains

class I SH3 motifs recognize RKXXPXXP motifs. E.g. : p60^c-Src
class II SH3 motifs recognize PZZPXR motifs. E.g. : Crk

unconventional (non-PXXP binding) SH3 domains. E.g. : Fyb, Pex13p.

WW (Trp-Trp) domains (three-stranded b-sheet) bind to Pro-rich sequences. E.g. in YAP, Nedd4, FBP.

Phospholipid-binding domains

C1 (Cys-rich 1) domains (2 b-sheets, which are pulled apart to form a cavity, and a short C-terminal a-helix) bind to diacylglycerol (DAG) and phorbol esters. E.g. in n-Chimaerin, cPKCs and nPKCs, DAGK, c-Raf.
phosphatidylinositol (PtdIns) phospholipids (phosphoinositides (PIs)-binding domains (see also Phosphoinositol lipids metabolism )

C2 (Cys-rich 2 / PKC conserved region 2) domains (2, 4-stranded b-sheets creating 3 loops at the top of the domain and 4 at the bottom) bind to acidic phospholipids in a Ca²⁺ (in)dependent manner. E.g. in PKCb, synaptotagmin.
FYVE (Fab-1, YGL023, Vps27 and EEA1) domains (a long loop at the very N-terminus followed by 2 Zn²⁺-binding clusters, 2 pairs of ds antiparallel b-sheets and a C-terminal a-helix) bind PI-3-P. E.g. in EEA1, Hrs, SARA, Vps27.
ENTH (Epsin NH₂-terminal homology) domains bind
PH (Pleckstrin-homology) domains (a b-barrel composed of 2 roughly perpendicular, anti-parallel b-sheets and a C-terminal a-amphipathic-helix) bind inositol phosphate ligands (PI-4,5-P₂, PI-3,4-P₂ or PI-3,4,5-P₃) and, for some, the bg subunits of heterotrimeric G-proteins. E.g. in Dbl, Ost, Ect2, Tim, Vav, Lbc, Cdc24, Bcr, Abr, Ras-GRF, PL-Cd, mSos1, Btk, C3G, Tiam-1, FGD1, Grp1, Akt/PKB.
PX (Phox homology) domains : in general conservation between PX domains is relatively low, although they do contain 2 highly conserved sequence motifs (R/K)(R/K)(Y/F)xxFxxLxxxL and R(R/K)xxLxx(Y/F) (where x in any amino acid residue). The domain is composed of 2 lobes (a-lobe and b-lobe) with a binding cleft between the lobes containing a pair of conserved binding motifs. Specificity for a particular PI may be determined in part by the orientation and context of 2 motifs : RR(Y/F) (basic motif I) and R(R/K) (basic motif II). Penetration of the PX domain into the membrane may orient basic motifs I and II toward the inositol phosphates at the D3, D4, and D1 positions. The PX domains that bind polyphosphorylated PIs may have additional basic elements in their binding sites to coordinate additional phosphates.
tubby domains

Apoptotic proteins domains

DD (death domains, 6 helical bundle with 3 stacked pairs of helices packed in an antiparallel manner) heterodimerize with the DD of distinct proteins, including adaptor proteins, bringing variuos components into a larger signaling complex. E.g. in DAPK, Fas, TRAILR1, FADD, RIP, TNFR5, TRADD, RAIID.
DED (death effector domains, 6 antiparallel a-helices) mediate homotypic interaction between the procaspase DED and a second DED in an adaptor molecule that is directly associated with TNF receptors. E.g. in procaspases , FLIP, FADD.
CARD (caspase recruitment domains, 6 helix bundle with Greek key topology) mediate the association of adaptor proteins and procaspases through heterodimerization of the respective CARDs. E.g. in RAIID, Apaf-1, CARDIAK, procaspases.
BH1-4 (Bcl-2 homology) domains (2 central a-helices (a5 (BH1) and a6) flanked on one side by a3 and a4 and on the other by a1 (BH4), a2 (BH3) and a7 (BH2)) mediate homodimerization (head-to-tail interaction) and heterodimerization (tail-to-tail interaction). E.g. : Bcl-2 family members .

Proteolysis domains

F-box (3 helices: the H1 helix packs orthogonally with the H2-H3 antiparallel pair) acts as adaptor components of the modualr E3 Ub ligase SCF complex that functions in phosphorylation mediated ubiquitination. E.g. in Cdc4, Grr12, TrCp, Skp1, Rbx1.
HECT (Homologous to the E6AP C-terminus) domains (bilobal structure with a broad catalytic cleft at the junction of the 2 lobes) bind specific E2s. E.g. in HECT-class E3 Ub ligases, Nedd4, Smurf1, Wwp2, E6AP, HectrH7, HectH6(p532).
RING domains (a CX₂CX_(9-39)CX_(1-3)HX_(2-3)C/HX₂CX_(4-48)CX₂C consensus sequence with the Cys and His representing Zn²⁺-binding residues). E.g. in RING class E3 Ub ligases (Hrt1/Roc1/Rbx1, APC1, Cbl, RAD5, RAD6, HHARI, Mdm2), TF (TIF1b, PML-RAR family, NFX1, XPRF), Midline-2, Lnx, TRAF-5, IAP-3.

RING-HC : a Cys occupies the fifth coordination site
RING-H2 : a His occupies the fifth coordination site

Dimerization domains

PDZ (PSD-95, Dlg and ZO-1/2) domains (a b-sandwich of 5-6 b-strands and 2 a-helices) mediate homodimerization or heterodimerization (head-to-tail interaction). E.g. in PSD-95, NMDA_B, Kvl1.4, nNOS.
SAM (strerile a motif) domains (5 helix bundle) mediate homo and heterodimerization. E.g. in CNK, EPH RTK, slp 76, Neurabin.
TIR (Toll/IL-1 receptor ) domain . E.g. in TLRs , IL-1R , IL-18R , MyD88 and TIRAP.

Domains with undefined functions

ANK (ankyrin) domain (pair of antiparallel a-helices stacked side by side and connected by a series of intervening b-hairpin motifs). E.g. in Ankyrin, Shank, ILK, DAPK, 53BP2, p16^INK4a, p19^INK4d, GABPa.
ARM (armadillo) domain (3 a-helices: a short helix is followed perpendicularly by 2 longer helices which pack against each other in an antiparallel fashion). E.g. in b-catenin, desmoplakin III, APC, importin-a.
WD40 domains (a propeller-like structure with 7 baldes where each blade is composed of a 4-stranded antiparallel b-sheet). E.g. in Gb subunit, Prp4, Sec13, Tup1, Sec13.

Miscellaneous domains

CUB : a domain containing peptide sequences found in the complement components, C1r/C1s, a sea urchin protein, and a bone morphogenic protein
Dbl-homology (DH) domain is present in GNRPs / GEFs / GDSs and usually is immediately followed by a PH domain. E.g. in Dbl, Ost, Ect2, Tim, Vav, Lbc, Cdc24, Bcr, Abr, Ras-GRF, Sos, C3G, Tiam-1, FGD1.
EF-hand (2 perpendicular 10 to 12 residues a-helices with a 12-residue loop region between, forming a single Ca²⁺-binding site (HLH)). E.g. in calretinin, calcineurin b-subunit, T-plastin, CaM, S-100, recoverin, calbindin, parvalbumin.

regulatory EF-hand motifs undergo conformational change after Ca²⁺ binding.
structural EF-hand motifs do not undergo significant conformational change after Ca²⁺ binding.

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