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Structural Basis for the Interaction Between Dynein Light Chain1 And

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Structural Basis for the Interaction Between Dynein Light Chain1 And Structural basis for the interaction between dynein light chain 1 and the glutamate channel homolog GRINL1A Marı´a F. Garcı´a-Mayoral1,Mo´ nica Martı´nez-Moreno2, Juan P. Albar3, Ignacio Rodrı´guez-Crespo2 and Marta Bruix1 1 Departamento de Espectroscopı´a y Estructura Molecular, Instituto de Quı´mica-Fı´sica Rocasolano, Consejo Superior de Investigaciones Cientificas (CSIC), Madrid, Spain 2 Departamento de Bioquı´mica y Biologı´a Molecular I, Universidad Complutense, Madrid, Spain 3 Proteomics Facility, Centro Nacional de Biotecnologı´a, Consejo Superior de Investigaciones Cientı´ficas, Madrid, Spain Keywords Human dynein light chain 1 (DYNLL1) is a dimeric 89-residue protein that dynein light chain; glutamate channel is known to be involved in cargo binding within the dynein multiprotein homolog; NMR; protein–protein interactions complex. Over 20 protein targets, of both cellular and viral origin, have been shown to interact with DYNLL1, and some of them are transported Correspondence I. Rodrı´guez-Crespo, Departamento de in a retrograde manner along microtubules. Using DYNLL1 as bait in a Bioquı´mica y Biologı´a Molecular I, yeast two-hybrid screen with a human heart library, we identified Universidad Complutense, 28040 Madrid, GRINL1A (ionotropic glutamate receptor N-methyl-d-aspartate-like 1A), Spain a homolog of the ionotropic glutamate receptor N-methyl d-aspartate, as a Fax: +34 913944159 DYNLL1 binding partner. Binding of DYNLL1 to GRINL1A was also Tel: +34 913944137 demonstrated using GST fusion proteins and pepscan membranes. Progres- E-mail: [email protected] sive deletions allowed us to narrow the DYNLL1 binding region of M. Bruix, Departamento de Espectroscopı´a y Estructura Molecular, Instituto de GRINL1A to the sequence REIGVGCDL. Combining these results with Quı´mica-Fı´sica Rocasolano, CSIC, Serrano NMR data, we have modelled the structure of the GRINL1A–DYNLL1 119, 28006 Madrid, Spain complex. By analogy with known structures of DYNLL1 bound to BCL-2- Fax: +34 915642431 interacting mediator (BIM) or neuronal nitric oxide synthase (nNOS), the Tel: +34 917459511 GRINL1A peptide also adopts an extended b-strand conformation that E-mail: [email protected] expands the central b-sheet within DYNLL1. Structural comparison with the nNOS–DYNLL1 complex reveals that a glycine residue of GRINL1A (Received 12 January 2010, revised 11 March 2010, accepted 15 March 2010) occupies the conserved glutamine site within the DYNLL1 binding groove. Hence, our data identify a novel membrane-associated DYNLL1 binding doi:10.1111/j.1742-4658.2010.07649.x partner and suggest that additional DYNLL1-binding partners are present near this glutamate channel homolog. Structured digital abstract l MINT-7713396: DYNLL1 (uniprotkb:P63167)andGRINL1A (uniprotkb:P0CAP1) bind (MI:0407) by nuclear magnetic resonance (MI:0077) l MINT-7713280, MINT-7713382: DYNLL1, (uniprotkb:P63167) physically interacts (MI:0915) with GRINL1A (uniprotkb:P0CAP1)bytwo hybrid (MI:0018) l MINT-7713416, MINT-7713439: GRINL1A (uniprotkb:P0CAP1) binds (MI:0407)toDYNLL1 (uniprotkb:P63167)bypeptide array (MI:0081) l MINT-7713307: GRINL1A (uniprotkb:P0CAP1) binds (MI:0407)toDYNLL1 (uniprotkb:P63167) by pull down (MI:0096) Abbreviations DTT, dithiothreitol; DYNLL, dynein light chain; GKAP, guanylate kinase-associated protein; GRINL1A, ionotropic glutamate receptor N-methyl-D-aspartate-like 1A; GSH, reduced glutathione; GST, glutathione S-transferase; NMDA, N-methyl D-aspartate; nNOS, neuronal nitric oxide synthase; PAK1, p21-activated kinase 1; PSD, post-synaptic density. 2340 FEBS Journal 277 (2010) 2340–2350 ª 2010 The Authors Journal compilation ª 2010 FEBS M. F. Garcı´a-Mayoral et al. DYNLL1 and GRINL1A interaction Introduction Dynein light chain, which has two isoforms termed receptors for either glycine or c-amino butyric acid DYNLL1 and DYNLL2 in mammals, is a small co-localize with the post-synaptic scaffolding protein dimeric protein that was initially described as a mem- gephyrin, another DYNLL1-associated protein [19,20]. ber of the myosin V [1,2] and dynein molecular motors Our proteomic studies have shown that, in rat brain, [3–5]. Originally, DYNLL1 was thought to bind to cer- DYNLL1 can associate with several NMDA receptors, tain protein cargos and transport them in a retrograde such as the NR3A-2 isoform [19]. manner along microtubules, bound to the dynein In this paper, we describe the screening of a human machinery. However, DYNLL1 can also be found in heart library using human DYNLL1 as bait. Several its soluble form and not associated with the large independent clones of the potential ionotropic gluta- dynein motor or microtubules [3,6]. In addition, cer- mate receptor-like gene N-methyl-d-aspartate-like 1A tain viruses are known to hijack the dynein machinery (GRINL1A) were retrieved corresponding to potential during their infective cycles, and several viral proteins DYNLL1-associated proteins. Then, using the pepscan are known to bind to DYNLL1 directly, such as rabies technique, we narrowed down the DYNLL1 binding virus P protein [7], African swine fever p54 protein [8] site, and showed that it is localized close to the cytosolic or Ebolavirus protein VP35 [9]. C-terminus of GRINL1A. Further complementary Numerous crystal and NMR atomic structures of approaches, including GST fusion, yeast two-hybrid dynein, both in the presence and absence of peptide assays and NMR titrations, confirmed the interaction ligands, are now available [10–13]. Sequence inspection and allowed fine mapping of the DYNLL1 binding site of DYNLL1-associated proteins followed by yeast within GRINL1A. Finally, all the experimental evi- two-hybrid assay, pepscan, site-directed mutagenesis dence was combined to build a structural model of and pull-down assays have revealed that DYNLL1 DYNLL1 bound to a GRINL1A peptide. associates with its target proteins essentially through the sequence motifs (R K)STQT and (K R)(D E)- ⁄ ⁄ ⁄ Results TGIQVDR [11,14,15]. In both cases, the polypeptide stretches that associate with DYNLL1 adopt an Identification of GRINL1A as a new extended conformation and form an additional DYNLL1-interacting protein b-strand that extends a pre-formed b-sheet, with the glutamine residue occupying an invariant position in Human DYNLL1 was fused in-frame to the binding the DYNLL1 binding groove. domain of GAL4 in the prey vector pGBT9, which DYNLL1 and DYNLL2 are also known to associ- was then used to transform yeast. After mating with ate on the cytosolic face of the plasma membrane, a yeast pre-transformed human heart library, mostly at the post-synaptic density, where they seem positive clones were selected and analysed by auto- to be involved in protein clustering in the proximity of mated DNA sequencing. Several overlapping clones the N-methyl d-aspartate (NMDA) receptor–post- were identified that included residues 144–463 of the synaptic density 95 (PSD-95) complex. For instance, human GRINL1A gene (Fig. 1A, accession number DYNLL2, and to a lesser extent DYNLL1, bind to a GI:238064959), which encodes a protein of 463 amino PSD-95-associated protein guanylate kinase domain- acids homologous to ionotropic glutamate receptors associated protein (GKAP) [16]. DYNLL1 also binds [21]. In order to identify potential DYNLL1 binding to neuronal nitric oxide synthase (nNOS), another sites within the GRINL1A sequence, the pepscan assay PSD-95-associated protein also present in the post-syn- was used. Overlapping dodecapeptides covering resi- aptic density [17,18]. Likewise, at inhibitory synapses, dues 156–466 of the prey protein were synthesized on A Fig. 1. Identification of GRINL1A as a DYNLL1-interacting protein and fine map- ping of the binding site. (A) Using a yeast two-hybrid screen, residues 144–463 of GRINL1A (C-terminal end) were shown to B bind to DYNLL1. (B) Pepscan analysis of the putative DYNLL1 binding site within the GRINL1A sequence. FEBS Journal 277 (2010) 2340–2350 ª 2010 The Authors Journal compilation ª 2010 FEBS 2341 DYNLL1 and GRINL1A interaction M. F. Garcı´a-Mayoral et al. a cellulose membrane, which was subsequently incu- A bated with purified recombinant DYNLL1. The bind- ing assay of DYNLL1 to GRINL1A revealed three potential binding regions, which are all close to the C-terminus of the protein (Fig. 1B). The three stretches comprised spot C4 [residues ASASLRERIRHL(342– 353)], spot C30 [residues TREIGVGCDLLP(420–431)] and spot D7 [residues VMPSRNYTPYTR(441–452)]. None of the peptides has a consensus DYNLL1-bind- ing site such as KSTQT or KDTGIQVDR [14,15], and no glutamine residues were found in these three positive spots. We considered spot C4 to be a false-positive, and B discarded it on the basis that peptides enriched in His, Lys and Arg amino acids typically bind to the antibody against hexahistidine used in the develop- ment of the pepscan assay. With that in mind, we fused the 100 C-terminal amino acids of GRINL1A (residues 363–463) to glutathione S-transferase (GST), and performed an in vitro binding assay to DYNLL1 (Fig. 2A). Purified GST–GRINL1A(363- 463) was bound to a glutathione–agarose resin, and a solution of purified recombinant DYNLL1 was C passed through the column. Elution of GST– GRINL1A(363–463) from the column using reduced glutathione (GSH) allowed us to detect DYNLL1 associated with GRINL1A by Coomassie staining (Fig. 2A, lanes B and C) or by using DYNLL1- specific antibodies (data not shown). This observa- tion demonstrates that the binding site of DYNLL1 within GRINL1A is located between residues 363 and 463. DYNLL1 did not interact with GST alone bound to the glutathione–agarose resin (data not Fig. 2. Binding of DYNLL1 to a GST–GRINL1A construct and fine shown). Next, we analysed this interaction in detail mapping of the binding site. GST–GRINL1A(363-463) was using a yeast two-hybrid approach, with wild-type expressed and purified in Escherichia coli, and extensively dialy- DYNLL1 fused to the bait vector pGBT9 and vari- sed. (A) Purified protein was loaded onto a GSH–agarose resin.
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