Microtubule-dependent retrograde transport of bovine immunodeficiency virus

Sai, Yang; Qiao, Wentao; Guo, Tingting; Tan, Juan; Li, Zhe; Chen, Yan; Li, Xin; Li, Yue; Zhou, Jun; Chen, Qimin

doi:10.1111/j.1462-5822.2010.01453.x

Cited by 31 publications

(37 citation statements)

References 17 publications

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“…Higher apparent affinity of DYNLL binding to dimeric protein fragments was first noted by studying DYNLL2 and myoVa interactions (2) and later attributed to avidity (15). This hypothesis questioned the original proposal of heterodimeric cargo adapter role of DYNLL on dynein and myoVa motor complexes (6,7,21,(55)(56)(57)(58).…”

Section: Fine-tuning Of Affinities Is Achieved Through Diversity Of Bmentioning

confidence: 97%

Affinity, Avidity, and Kinetics of Target Sequence Binding to LC8 Dynein Light Chain Isoforms

Radnai

Rapali

Hódi

et al. 2010

Journal of Biological Chemistry

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LC8 dynein light chain (DYNLL) is a highly conserved eukaryotic hub protein with dozens of binding partners and various functions beyond being a subunit of dynein and myosin Va motor proteins. Here, we compared the kinetic and thermodynamic parameters of binding of both mammalian isoforms, DYNLL1 and DYNLL2, to two putative consensus binding motifs (KXTQTX and XG(I/V)QVD) and report only subtle differences. Peptides containing either of the above motifs bind to DYNLL2 with micromolar affinity, whereas a myosin Va peptide (lacking the conserved Gln) and the noncanonical Pak1 peptide bind with K d values of 9 and 40 M, respectively. Binding of the KXTQTX motif is enthalpy-driven, although that of all other peptides is both enthalpy-and entropy-driven. Moreover, the KXTQTX motif shows strikingly slower off-rate constant than the other motifs. As most DYNLL partners are homodimeric, we also assessed the binding of bivalent ligands to DYNLL2. Compared with monovalent ligands, a significant avidity effect was found as follows: K d values of 37 and 3.5 nM for a dimeric myosin Va fragment and a Leu zipper dimerized KXTQTX motif, respectively. Ligand binding kinetics of DYNLL can best be described by a conformational selection model consisting of a slow isomerization and a rapid binding step. We also studied the binding of the phosphomimetic S88E mutant of DYNLL2 to the dimeric myosin Va fragment, and we found a significantly lower apparent K d value (3 M). We conclude that the thermodynamic and kinetic fine-tuning of binding of various ligands to DYNLL could have physiological relevance in its interaction network.

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Section: Fine-tuning Of Affinities Is Achieved Through Diversity Of Bmentioning

confidence: 97%

Affinity, Avidity, and Kinetics of Target Sequence Binding to LC8 Dynein Light Chain Isoforms

Radnai

Rapali

Hódi

et al. 2010

Journal of Biological Chemistry

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“…Together, the above findings support the conclusion that the DYNLL1-IN interaction is required for the proper uncoating of HIV-1. Since some earlier studies implicated DYNLL1 in cargo recruitment to the dynein complex during retrograde transport (17,18,67), we were interested in examining the potential role of interaction between IN and DYNLL1 in HIV-1 association with the dynein complex. Since dynein adapter proteins recruit cargo to the dynein complex through the interaction with DIC1/2 ( Fig.…”

Section: Dynll1 But Not P150mentioning

confidence: 99%

“…Glued have been implicated in cargo recruitment to the dynein complex during retrograde transport (15)(16)(17)(18). The dynein complex is a microtubule (MT)-associated protein complex that mediates retrograde transport of macromolecules in the cytoplasm (19).…”

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confidence: 99%

“…For example, DYNLL1 interacts with specific rabies virus phosphoprotein and contributes to the viral gene expression (26)(27)(28). Also, DYNLL1 interacts with the CA protein of bovine immunodeficiency virus (BIV) and contributes to retrograde transport of BIV (18). DYNLT1 interacts with the CA protein of human papillomavirus type 16 (HPV-16) and contributes to HPV-16 replication at an unknown replication step(s) (29).…”

mentioning

confidence: 99%

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Human Immunodeficiency Virus Type 1 Employs the Cellular Dynein Light Chain 1 Protein for Reverse Transcription through Interaction with Its Integrase Protein

Jayappa

Wang

et al. 2015

J Virol

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In this study, we examined the requirement for host dynein adapter proteins such as dynein light chain 1 (DYNLL1), dynein light chain Tctex-type 1 (DYNLT1), and p150Glued in early steps of human immunodeficiency virus type 1 (HIV-1) replication. We found that the knockdown (KD) of DYNLL1, but not DYNLT1 or p150 Glued T he steps of early stage human immunodeficiency virus type 1 (HIV-1) replication include virus entry, uncoating, reverse transcription, intracytoplasmic retrograde transportation (i.e., the migration of HIV from the cytoplasmic periphery to the perinuclear space), nuclear import, and genomic integration (reviewed in reference 1). Following HIV-1 entry into the cell, viral genomic RNA and associated proteins are released into the cytoplasm as a ribonucleoprotein complex referred as the reverse transcription complex (RTC). Within the RTC, HIV-1 genomic RNA is reverse transcribed into a cDNA, which then forms a highmolecular-weight preintegration complex (PIC). HIV-1 cDNA enters the nucleus as a part of PIC by active nuclear import and subsequently integrates into the host cell genome (reviewed in reference 2).HIV-1 utilizes various cellular proteins for replication mostly by interacting with its viral proteins. Genome-wide small interfering RNA (siRNA)/short hairpin RNA (shRNA) screening as well as other functional studies have uncovered a large number of host proteins with putative roles in HIV-1 replication (reviewed in references 3, 4, and 5). Additionally, functional studies from our laboratory, as well as from other groups, have uncovered key viral and cellular protein interactions that promote successful HIV-1 nuclear import and integration (reviewed in references 2 and 6). However, molecular events associated with HIV-1 reverse transcription, uncoating, or retrograde transport in the cytoplasm are not well understood. To date, evidence suggests that gem-associated protein 2 (Gemin2) interacts with HIV-1 integrase (IN) in target cells and contributes to reverse transcription by an unknown mechanism(s) (7,8). Similarly, accumulated evidence suggests that cyclophilin A (CypA) and peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (prolyl isomerase Pin1) proteins interact with HIV-1 capsid (CA) protein in target cells and facilitate the proper uncoating of HIV-1 (9, 10). In addition, some other cellular factors with putative roles in HIV-1 reverse transcription and uncoating have been described in recent studies (11)(12)(13)(14). Although the exact mechanism(s) by which these cellular factors contribute to HIV-1 reverse transcription and/or uncoating is not very clear, the accumulated evidence so far clearly suggests a key role for cellular cofactors in HIV-1 uncoating and reverse transcription.Dynein adapter proteins such as dynein light chain 1 (DYNLL1, LC8, DLC1), dynein light chain Tctex-type 1 (DYNLT1), and p150Glued have been implicated in cargo recruitment to the dynein complex during retrograde transport (15-18). The dynein complex is a microtubule (MT)-associated protein c...

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“…nNOS (21,22), Pak1 (23)(24)(25), Bmf (26), Bim (27), Bassoon (28), GKAP (29), and viral proteins (30,31)), it was hypothesized that DYNLL may provide direct physical linkage between the motor and the cargos (26,28,29). However, as the majority of the binding partners (including the motors) are dimeric, and therefore they are bivalent ligands of LC8 and the formation of highly stable dimer-to-dimer complexes is preferred (18).…”

mentioning

confidence: 99%

DYNLL2 Dynein Light Chain Binds to an Extended Linear Motif of Myosin 5a Tail That Has Structural Plasticity

Bodor¹,

Radnai²,

Hetényi

et al. 2014

Biochemistry

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LC8 dynein light chains (DYNLL) are conserved homodimeric eukaryotic hub proteins that participate in diverse cellular processes. Among the binding partners of DYNLL2, myosin 5a (myo5a) is a motor protein involved in cargo transport. Here we provide a profound characterization of the DYNLL2 binding motif of myo5a in free and DYNLL2 bound form by using NMR spectroscopy, Xray crystallography and molecular dynamics simulations. In the free form the DYNLL2 binding region, located in an intrinsically disordered domain of the myo5a tail, has a nascent helical character. The motif becomes structured and folds into a β-strand upon binding to DYNLL2. Despite all differences of the myo5a sequence from the consensus binding motif, it accommodates into the same DYNLL2 binding groove as all other partners do. Interestingly, while the core motif shows similar interaction pattern in the binding groove as seen inother complexes, the flanking residues make several additional contacts, thereby lengthening the binding motif. The N-terminal extension folds back and partially blocks the free edge of the β-sheet formed by the binding motif itself. The C-terminal extension contacts the dimer interface and interacts with symmetry related residues of the second myo5a peptide. The involvement of flanking residues of the core binding site of myo5a could modify the quaternary structure of the full-length myo5a and affect its biological functions. The presented structural data widen our understanding of the diverse partner recognition of DYNLL proteins and provide an example of a Janus-faced linear motif. 4The LC8 dynein light chains were originally described as the smallest subunit of the microtubuleassociated cytoplasmic dynein motor complex.They show a highly conserved amino acid sequence throughout evolution and they were later shown to bind to more than 70 other proteins involved in various biological processes, therefore they are now considered hub proteins (1, 2).Vertebrates contain two closely related LC8 paralogs, DYNLL1 and DYNLL2 with partially overlapping functions(1). Under physiological conditions LC8proteins arestable homodimers (3).Atomic resolution structureswere determined both for the apo and ligand-bound form using X-ray crystallographyand NMR spectroscopy (4-6). Five β-strands make up two core β-sheets; one sideof each sheet is flanked by two α-helices, and the otherside forms the dimer interface. The β3-strand of one subunit pairs to theβ2"-strandof the other subunitin an antiparallel mode; and the dimer is stabilized by interface contacts through hydrophobic interactions and side chain H-bonds. Two equivalent grooves are formed and they represent the target binding pockets of the dimer. The primary transcript of the human MYO5A geneis processed by alternative splicing (13). Three exons 5 within the tail domain (B, D, and F) are expressed in a cell type-specific manner; the predominant melanocyte-and brain-specific isoforms contains exons D, F, and exon B, respectively (13). The exon pattern of myo5a tail lik...

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Microtubule-dependent retrograde transport of bovine immunodeficiency virus

Cited by 31 publications

References 17 publications

Affinity, Avidity, and Kinetics of Target Sequence Binding to LC8 Dynein Light Chain Isoforms

Affinity, Avidity, and Kinetics of Target Sequence Binding to LC8 Dynein Light Chain Isoforms

Human Immunodeficiency Virus Type 1 Employs the Cellular Dynein Light Chain 1 Protein for Reverse Transcription through Interaction with Its Integrase Protein

DYNLL2 Dynein Light Chain Binds to an Extended Linear Motif of Myosin 5a Tail That Has Structural Plasticity

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