Scholarly article on topic 'Integrin triplets of marine sponges in the murine and human MHCI-CD8 interface and in the interface of human neural receptor heteromers and subunits'

Integrin triplets of marine sponges in the murine and human MHCI-CD8 interface and in the interface of human neural receptor heteromers and subunits Academic research paper on "Biological sciences"

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Academic research paper on topic "Integrin triplets of marine sponges in the murine and human MHCI-CD8 interface and in the interface of human neural receptor heteromers and subunits"

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RESEARCH Open Access

Integrin triplets of marine sponges in the murine and human MHCI-CD8 interface and in the interface of human neural receptor heteromers and subunits

Alexander O Tarakanov1* and Kjell G Fuxe2

Abstract

Based on our theory, main triplets of amino acid residues have been discovered in cell-adhesion receptors (integrins) of marine sponges, which participate as homologies in the interface between two major immune molecules, MHC class I (MHCI) and CD8ap. They appear as homologies also in several human neural receptor heteromers and subunits. The obtained results probably mean that neural and immune receptors also utilize these structural integrin triplets to form heteromers and ion channels, which are required for a tuned and integrated intracellular and intercellular communication and a communication between cells and the extracellular matrix with an origin in sponges, the oldest multicellular animals.

Keywords: Neural receptor-receptor interactions, Receptor interface, Marine sponges, Triplet homologies

Introduction

Based on a mathematical approach, Tarakanov and Fuxe (2010, 2011) have deduced a set of triplet homologies (so called 'triplet puzzle') that may be responsible for proteinprotein interactions, including receptor heteromers and human immunodeficiency virus (HIV) entry. For example, the triplet of amino acid residues ITL (Ile-Thr-Leu) appears in both receptors of any of six receptor heteromers: GABAB1-GABAB2 (GABAB receptor), GABAB1-mGluR1, GABAB1-CXCR4, CXCR4-CCR2, 5HT1B-5HT1D, and MHC class I MHCI-CD8. At the same time, this triplet ITL does not appear in both receptors of any of known non-heteromers (GABAB2-A2A, A2A-D1, A1-D2, NTSR1-D1, TSHR-D2, and CD4-D2; see Tarakanov and Fuxe 2010). According to recent biochemical studies (Borroto-Escuela et al. 2010, 2011, 2012a,b; Romero-Fernandez et al. 2011), such triplets exist in the interacting domains forming the receptor interface. Furthermore, a 'guide-and -clasp' manner of receptor-receptor interactions has been proposed where the 'adhesive guides' may be the triplet

* Correspondence: tar@iias.spb.su

1Russian Academy of Sciences, St. Petersburg Institute for Informatics and Automation, Saint Petersburg, Russia

Full list of author information is available at the end of the article

homologies (Tarakanov and Fuxe, 2010). According to recent bioinformatic studies (Tarakanov et al. 2012 a,b,c,d), several triplet homologies of such receptor heteromers in human brain may be the same as in cell-adhesion receptors of marine sponges, known to be highly conserved from the lowest metazoa to vertebrates (Gamulin et al. 1994; Muller 1997; Pancer et al. 1997; Buljan and Bateman 2009). Interactions between such triplets probably represent a general molecular mechanism for receptor-receptor interactions (Fuxe et al 2012) and may play an important role in human learning (Agnati et al. 2003) and some diseases (Tarakanov et al. 2009).

In the current paper, many of such triplets have been found in integrins of marine sponges together with human alpha and beta integrins. This means that such triplet homologies may play a role in alpha-beta heterodimeric complexes forming integrin receptors and interact with extracellular matrix proteins (Barczyk et al. 2010). Of especial interest is that the same integrin triplets exist also in the murine and human MHCI interface with CD8, in human neural receptors and in the interface of both protomers of several receptor heteromers. The presence of such triplet homologies in several receptor subunits building up the neuromuscular nicotinic cholinergic

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© 2013 Tarakanov and Fuxe; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, anc reproduction in any medium, provided the original work is properly cited.

Table 1 Data on proteins used

Protein Species Type Accession code

ITGA Sponge (Geodia cydonium) Metazoan adhesion receptor subunit Integrin-a CAA65943

ITGB Sponge (Geodia cydonium) Metazoan adhesion receptor subunit Integrin-p CAA77071

ITGB4 Sponge (Marichromatium purpuratum) Metazoan adhesion receptor subunit Integrin-p4 ZP_08774040

MHCI Mouse (Mus musculus) H-2 class I histocompatibility antigen NP_001001892

CD8a Mouse T-cellsurface glycoprotein chain CD8a NP_001074579

CD8b Mouse T-cellsurface glycoprotein chain CD8p NP_033988

MHCI Human (Homo sapiens) H-2 class I histocompatibility antigen AAA59599

CD8a Human T-cellsurface glycoprotein chain CD8a NP_001139345

CD8b Human T-cellsurface glycoprotein chain CD8p NP_757362)

CXCR4 Human Chemokine receptor P61073

TSHR Human Thyroid stimulating hormone receptor NP_000360

FGFR1 Human Fibroblast growth factor receptor NP_075598

5HT1A Human Serotonin receptor AAH69159

Collagen Human Matrix protein P02452

ITGAIIB Human Integrin receptor subunit-aIIb P08514

ITGAL Human Integrin receptor subunit-aL P20701

ITGAM Human Integrin receptor subunit-aM NP_001139280

ITGAV Human Integrin receptor subunit-aV EAX10934

ITGAX Human Integrin receptor subunit-aX NP_000878

ITGB2 Human Integrin receptor subunit-p2 NP_000202

ITGB3 Human Integrin receptor subunit-p3 NP_000203

ITGB4 Human Integrin receptor subunit-p4 NP_000204

ITGB5 Human Integrin receptor subunit-p5 NP_000205

ITGB6 Human Integrin receptor subunit-p6 P18564

ITGB8 Human Integrin receptor subunit-p8 P26012

ACHA Human Acetylcholine receptor subunit-a P02708

ACHB Human Acetylcholine receptor subunit-p P11230

ACHD Human Acetylcholine receptor subunit-5 Q07001

ACHE Human Acetylcholine receptor subunit-£ Q04844

mGluRl Human Metabotropic glutamate receptor NP_000829

GABAB2 Human y-aminobutyric acid receptor subunit-2 O75899

GABAB1 Human (Homo sapiens) y-aminobutyric acid receptor subunit-1 NP_001461

GABAB1 Mouse (Mus musculus) NP_062312

GABAB1 Norway rat (Rattus norvegicus) NP_112290

GABAB1 Western clawed frog (Xenopus (Silurana) tropicalis) NP_001107291

GABAB1 Green puffer (Tetraodon nigroviridis) uniprot/Q4S9D9

GABAB1 Zebrafish (Danio rerio) NP_001070794

GABAB1 African malaria mosquito (Anopheles gambiae) uniprot/Q7PME5

GABAB1 Drosophila pseudoobscura XP_001357356

GABAB1 Human body louse (Pediculus humanus corporis) XP_002430445

GABAB1 Caenorhabditis elegans ACE63490

Table 2 Example of integrin triplets of marine sponges in murine and human proteins

Protein Species Type LLG GLL ITL RPA GDR RDG DGR

ITGA Sponge ntegrin-a - - + + + - -

ITGB Sponge ntegrin-ß + + - - - - -

ITGB4 Sponge ntegrin-ß - - - - - + +

MHC Class I Mouse Immune receptor + - + + - - +

CD8a Mouse Immune receptor + - + - - - -

CD8b Mouse Immune receptor - - - - - - -

MHC Class I Human Immune receptor + - + + - + +

CD8a Human Immune receptor - - + + - - -

CD8b Human Immune receptor - + + - - - -

CXCR4 Human Immune receptor - - + - - - -

TSHR Human Endocrine receptor - - - + - - -

FGFR1 Human Receptor tyrosine kinase - - - + - - -

5HT1A Human Neuralreceptor + - - - - - -

Collagen Human Matrix protein - - - - + + +

ITGAIIB Human ntegr n-a + + - - - + +

ITGAL Human ntegr n-a - + - - - - -

ITGAM Human ntegr n-a + + - - - - -

ITGAV Human ntegr n-a + + - - - - -

ITGAX Human ntegr n-a + + + - + -

ITGB2 Human ntegr n-ß - + - - - - +

ITGB3 Human ntegr n-ß - + - - - - +

ITGB4 Human ntegr n-ß + - - - - - -

ITGB5 Human ntegr n-ß + - - - - + -

ITGB6 Human ntegr n-ß - + - - - - -

ITGB8 Human ntegr n-ß - + - - + - -

ACHA Human Neural receptor subunit + - - - - - -

ACHB Human Neural receptor subunit + - + + + - -

ACHD Human Neural receptor subunit - + + + - - -

ACHE Human Neural receptor subunit + + - - - - -

GABAB1 Human Neuralreceptor + + + - - - -

GABAB2 Human Neuralreceptor - + + - - - -

mGluRl Human Neuralreceptor - + + - - - -

(+ yes, - no).

r e i p C T3 . i

C 3' O IQ

NJ 00 00

Table 3 Example of integrin triplets of marine sponges in the protomers of human receptor heteromers and in subunits of the neuromuscular nicotinic receptor

Receptor heteromer Reference Function LLG GLL ITL RPA DGR

MHCI-CD8a Gao et al. (1997) Wang et al. (2009) Adaptive immune response - - # +-

MHC1-CD8b Wang et al. (2009) Adaptive immune response - - # --

CD8a-CD8b Wang et al. (2009) Coreceptor of T cells - - + --

ITGAIIB-ITGB3 Barczyk et al. (2010) RGD (Arg-Gly-Asp) receptor - # - -#

ITGAV-ITGB3 Barczyk et al. (2010) RGD receptor - # - --

ITGAV-ITGB5 Barczyk et al. (2010) RGD receptor # - - --

ITGAV-ITGB6 Barczyk et al. (2010) RGD receptor - # - --

ITGAV-ITGB8 Barczyk et al. (2010) RGD receptor - # - --

ITGAL-ITGB2 Barczyk et al. (2010) Leukocyte receptor - + - --

ITGAM-ITGB2 Barczyk et al. (2010) Leukocyte receptor - + - --

ITGAX-ITGB2 Barczyk et al. (2010) Leukocyte receptor - + - --

GABAB1-GABAB2 Marshall et al. (2001) Activation of the potassium channels and regulation of receptor trafficking - # # --

GABAB1-mGluR1 Hirono et al. (2001) Modulation of excitatory transmission - # + --

GABAB1-CXCR4 Guyon and Nahon (2007) Modulation of neuroendocrine systems - - # --

ACHA-ACHB Changeux et al. 1984 Part of the neuromuscular nicotinic receptor + - - --

ACHA-ACHE Changeux et al. 1984 Part of the neuromuscular nicotinic receptor + - - --

ACHB-ACHD Changeux et al. 1984 Part of the neuromuscular nicotinic receptor - - + #-

С Тз

NJ 00 00

(+ yes in both receptors, # may mediate their interaction, - no in any receptor).

4 О 8

ITGA_sponge 511

KHCI mouse 230

MHCI_human 233

CD8a mouse 210

CD8a_human 19S

CD8b_human 167

CXCR4_human 89

GABABl_human 343

GABAB2_tiuman 730

mGluRlJnuman 94

ACHD_human 175

ACHB_human 255

ITGA_spo nge 729

MHCI mouse 251

MHCI_human 254

CD8a_human 161

TSHR_human 1

FGFRl_human 361

ACHB_human 39

ACHD_human 212

ITGB4_sponge 128

MHCI mouse 123

MHCI_human 126

collagen_human 558

IT GA11B_human 32 8

ITGB3 human 281

BlTLVS^R [itltwql jitltwqr lsliitlicyh

lslvitlycnh

lcsfitlgllv llfvitlpfwa fssyitlvvlf fcstitlclvf llpnitlgsgl TAK^itlslkq pcilitllaif

¡SfrfrpaJJslt lvHtrpagSgt lv'irpagJrt

Pg&CRPAAGGA MRPAgLLQ ALiSBrPAVWTS

¡SssvrparJ|vg

¡slvhrparvnv

pafvdgrvagi bvgsdgrllrg gvgsdgrflrg pagqdgrpgpp gvNGDGRHgLL hialdgrlagi

Extracellular Contact CDSab

TM2 TM7 TM7

N-terminal

N-terminal TM1

Extracellular

N-terminal(exactly)

N-terminal N-terminal

Extracellular

Extracellular Extracellular

Figure 1 Example of the triplets ITL, RPA, and DGR (dark-shaded letters) in the integrins of marine sponges existing in the murine (underlined) and human MHCI-CD8 complex, human collagen (DGR triplet), and human receptor heteromers: TM1, TM2 and TM7 are the first, the second and the seventh transmembrane a-helices of ACHB, CXCR4, and GABAB (GABAB1-GABAB2 heteromer) receptors, respectively, and contain the ITL triplet. The RPA triplet is also found in the TSHR and FGFR1; the RPA but not the ITL triplet homologies are ir a position to contribute to the physicalinteraction between the beta and delta subunits of the neuromuscular nicotinic receptor (ACHB-ACHD); light-shaded letters are positively charged amino acids (R, K, and H), whereas dark-shaded white letters are negatively charged amino acids (D and E); bold letters are main players of leucine-rich motifs (L, S, and C).

receptors has also been demonstrated. At least one of the homologies may have a role in the intermolecular subunit interactions of this ion channel receptor.

Methods

Amino acid codes of receptors and other proteins have been obtained from the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov) and the Universal Protein Resource (http://www.uniprot.org). Table 1 summarizes data on proteins used. In abstract mathematical terms, any protein is just a word coded by a 20-letter alphabet where triplet is any 3-letter subword. Thus, triplet homology is any triplet which exists in both given words. Our theory of triplet puzzle supposes some basic set of triplets as a code that determines whether two receptors bind or not (Tarakanov and Fuxe 2010). None of the widely used software like Clustal (http://www.clustal.org/), AGGRESCAN (http://bioinf.uab. es/aggrescan/), accelrys (http://accelrys.com/), and so on seems to be able to deal with so specific and complicated combinatorial puzzle. Our original software has been developed to determine such basic set of triplet homologies from two given sets of protein-protein pairs (which bind and do

not bind). The core of this software is the computing of all triplet homologies between two given words (but not only their alignment like in the above mentioned Clustal). The method consists in forming the binary matrix of all one-letter homologies (which element is 1 if there is homology and 0 otherwise) and then filtering this matrix using rather specific rules of so called cellular automata (for example, see Tarakanov and Prokaev 2007; http://youtu.be/ 1DevThU5fyM).

No experimental research has been performed on humans and/or animals.

Results

The triplets ITL (Ile-Thr-Leu), RPA (Arg-Pro-Ala), DGR (Asp-Gly-Arg), LLG (Leu-Leu-Gly), and GLL (Gly-Leu-Leu) of the integrin receptors of marine sponges appear as homologies in murine and human MHCI, GABAB1, and human integrin receptor heteromers (see Tables 2 and 3, Figures 1 and 2). The triplets ITL (Ile-Thr-Leu) and DGR (Asp-Gly-Arg) are particularly interesting. For example, the triplet ITL is in the interface providing the binding between MHCI and CD8a|3 (Wang et al. 2009).

ITGB_sponge ITGB_sponge

MHCI mouse MHCInhuman ITGAV_human ITGB5_human ACHB_human ACHE_humart ACHA_human GABAB1_human

ITGB_sponge

CD8b_human

ITGAIIB_human

ITGB3_human

XTGAV_human

ITGB6_human

ITGAV_human

ITGB8_human

ITGAL_human

ITGAM_human

ITGAX_human

ITGB2_human

GABAB1_human

GABAB 2 _h uma n

mGluRl_human

ACHDjiuman

ACHE human

273 AG^GLLGGVIK

819 GlLLLLGILAL

98 ¡JLRTLLGYYNQ

9 LLLLLLGALAL

196 AJJRVLLGGPGS

317 FSLALLG{|KLA

5 AL LKLLGAL GA

7 GVLLLLGLLGR

451 t^HILLGVFML

778 GLLLLLG X FLA

272 FAG^GLLGGVI

170 PITLGLLVAGV

220 YYFLGLLAQAP

594 MSSNGLLCSGR

18 LLLSGUiLPLC

347 GATVGLLQKES

1000 AVLAGLLLLAV

693 TFLIGLLKVLI

1096 SGIGGLLLLLL

1113 SSVGGLLLLAL

1112 SSIGGLLLLÄL

9 LALVGIJiSLGC

77 4 YGYKGÜLLLG

661 YAYKGLLKLFG

757 LGYNGLLIMSC

S VLTLGLLAALA

9 LLLLGLLGRGV

Extracellular TM

N-terminal

Extracellular

Extracellular

N-terminal

N-terminal

Extracellular

Extracellular

Extracellular

N-terminal

Extracellular

N-terminal

N-terminal N-terminal

Figure 2 Example of the triplets LLG and GLL (dark-shaded letters) in the integrins of marine sponges, murine (underlined) and human MHC Class I and human receptor heteromers.

TM7 F L

GABABl HUMAN 836 FASLAIVFSSYITIiWLF

GAB ABl" MOUSE 835 FASLAIVFSSYIT1WLF

GAB ABl RAT 835 FASLAIVFSSYITLWLF

GAB ABl' _FROG 781 FSSLAIVFSAYITLWLF

GAB ABl" TETNG 444 FAS LAIVFSAYI Til WL F

GAB ABl" DANRE 429 FPLLFGTFNLVYWATYLN

GAB ABl" ANOGA 692 FVALAVIFCCFLSMLLIF

GAB ABl" DROPS 709 FVÄLAVIFCCFLSMLLIF

GAB ABl" LOUSE 705 FVSLSIIFCCFLSMALIF

GAB ABl" _CAEEL 700 FISLTVLICTYISVGLIY * * '

Figure 3 The triplet ITL (dark-shaded letters) during the evolution of GABAB1 subunit: CAEEL (Caenorhabditis elegans), LOUSE (Pediculus humanus corporis), DROPS (Drosophila pseudoobscura), ANOGA (Anopheles gambiae), DANRE (Danio rerio), TETNG (Tetraodon nigroviridis), FROG (Xenopus tropicalis), RAT (Rattus norvegicus), MOUSE (Mus musculus), and HUNAN (Homo sapiens); asterisk (*) marks homologies (F and L); quote (') marks leucine-like homologies (L and I); bold letters are main players of leucine-rich motifs (L, S, and C).

This triplet homology exists also in three GABAB1 receptor heteromers of human brain: GABAB1-GABAB2 forming the GABAB receptor (Marshall et al. 2001), GABAB1-mGluR1, and GABAB1-CXCR4 and may mediate the interaction in two of them (see Table 3 and Figure 1). In the first two heteromers also triplet GLL (Gly-Leu-Leu) may participate in the interaction (see Table 3 and Figure 2).

The triplet DGR (Asp-Gly-Arg) is in fact the inverse triplet of RGD (Arg-Gly-Asp) that provides the binding site for integrin RGD-binding receptors (see Table 3). Moreover, a small peptide ligand RGD (Arg-Gly-Asp) that mimics extracellular matrix protein binding to integrins also causes impairments in plasticity at glutamatergic synapses (Wiggins et al. 2011).

The evolution of the ITL triplet in the GABAB1 receptor subunit is displayed in Figure 3. In phylogeny, it appears to begin in fish (Tetraodon) and then continues to man, while it is missing in zebrafish (Danio rerio). Thus, the usefulness of the ITL triplet in recognition is rediscovered in the fish GABAB1 receptor.

Furthermore, the RPA triplet homology in the beta and delta interacting nicotinic subunits of the neuromuscular nicotinic receptor (see Changeux et al. 1984) is in a location

(N-terminal parts of ACHB and ACHD) where it may participate in forming part of their interface (see Figure 1 and Table 3).

Discussion

The triplet ITL (Ile-Thr-Leu) found in integrins of marine sponges is presented as a homology in the interface between MHC Class I and CD8a|3 heterodimer (coreceptor in T cells). It is postulated that this triplet homology can contribute to the formation of the MHCI-CD8 heteromeric complex which leads to a strong activation of the T cell by guiding the T-cell receptor into relevant self-MHC recognition (see Wang et al. 2009). Thus, it seems possible that the ITL triplet may have a critical role in the interaction between these two immune receptors which is necessary for appropriate T cell function. A mutation of the ITL triplet in these immune receptors will be of value to test this hypothesis. The indications have also been obtained that triplet homology ITL in the N-terminal of beta and delta nicotinic receptor subunits of the neuromuscular nicotinic receptor may help mediate their interaction in the subunit interface.

Conclusion

Integrin triplets of marine sponges found in the interface of human receptor heteromers and even in the interface between two major immune molecules MHCI-CD8 seem to confirm once more our theory. This triplet puzzle arose as a surprising merger of pure mathematics and most recent biochemical studies of receptor-receptor interactions. As a result, it appears that neural and immune receptor heteromers in humans may also utilize these structural elements originating in sponges, the oldest multicellular animals. Thus, the triplet puzzle may be an ancient and general mechanism for protein-protein recognition.

Competing interests

Both authors declare that they have no competing interests. Authors' contributions

AT carried out the mathematicalstudies and computations. KF carried out the biomedicalinterpretation of the results. Allauthors read and approved the finalmanuscript.

Acknowledgement

The authors have not received any support for this work. Author details

1Russian Academy of Sciences, St. Petersburg Institute for Informatics and Automation, Saint Petersburg, Russia. 2Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Received: 23 October 2012 Accepted: 11 March 2013 Published: 22 March 2013

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doi:10.1186/2193-1801-2-128

Cite this article as: Tarakanov and Fuxe: Integrin triplets of marine sponges in the murine and human MHCI-CD8 interface and in the interface of human neural receptor heteromers and subunits.

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