Unique Functional Properties of Conserved Arginine Residues in the Lentivirus Lytic Peptide Domains of the C-terminal Tail of HIV-1 gp41

Kuhlmann, Anne-Sophie; Steckbeck, Jonathan D.; Sturgeon, Timothy J.; Craigo, Jodi K.; Montelaro, Ronald C.

doi:10.1074/jbc.m113.529339

Cited by 9 publications

(6 citation statements)

References 55 publications

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“…This similarity is reflected in the BLOSUM analysis, which is widely employed for sequence alignment of protein sequences . In the context of certain peptides and proteins, however, it has also been previously recognized that lysine and arginine residues can sometimes be inequivalent. − Our results lead to the proposal that such inequivalence can arise from the distinct influences of ammonium versus guanidinium groups on the hydrophobic interactions mediated by adjacent nonpolar domains. The challenges involved in testing this proposal with α-peptide systems are highlighted by our recent results involving α-helical coiled-coil dimerization of α-peptides; those results suggest that differences in the α-helical propensities of Lys and Arg may also influence dimer stability.…”

Section: Discussionmentioning

confidence: 68%

“…The effects of lysine-to-arginine mutations have been explored in past studies. − In soluble proteins, such mutations are generally considered to be “conservative”, which is reflected in the BLOSUM analysis for alignment of protein sequences . In the context of some peptides and proteins, however, it has been observed that lysine and arginine residues can be inequivalent. − Our results lead to the proposal that one source of such inequivalence is the distinct influences of ammonium versus guanidinium groups on hydrophobic interactions mediated by the adjacent nonpolar domains. To our knowledge, this proposal has not been advanced by others.…”

Section: Introductionmentioning

confidence: 76%

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Cationic Side Chain Identity Directs the Hydrophobically Driven Self-Assembly of Amphiphilic β-Peptides in Aqueous Solution

et al. 2021

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Hydrophobic interactions mediated by nonpolar molecular fragments in water are influenced by local chemical and physical contexts in ways that are not yet fully understood. Here, we use globally amphiphilic (GA) β-peptides (GA-Lys and GA-Arg) with stable conformations to explore if replacement of β 3 -homolysine (βLys) with β 3 -homoarginine (βArg) influences the hydrophobically driven assembly of these peptides in bulk aqueous solution. The studies were conducted in 10 mM triethanolamine buffer at pH 7, where both βLys (ammonium) and βArg (guanidinium) side chains are substantially protonated. Comparisons of light scattering measurements and cryo-electron micrographs before and after the addition of 60 vol% MeOH indicate very different outcomes of the hydrophobically driven assembly of AcY-GA-Lys versus AcY-GA-Arg (AcY denotes an N-acetylated-β 3 -homotyrosine (βTyr) at each N-terminus). Nuclear magnetic resonance and analytical ultracentrifugation confirm that AcY-GA-Lys assembles into large aggregates in aqueous buffer, whereas AcY-GA-Arg at comparable concentrations forms only small oligomers. Titration of AcY-GA-Arg into aqueous solutions of AcY-GA-Lys reveals that the driving force for AcY-GA-Lys association is far stronger than that for AcY-GA-Arg association. We discuss these results in the light of past experimental observations involving single molecule force measurements with GA β-peptides and hydrophobically driven dimerization of conventional peptides that form a GA α-helix upon dimerization (but do not display the Lys versus Arg trend predicted by extrapolating from the earlier AFM studies with β-peptides). Overall, our results establish that the identity of proximal cationic groups, ammonium versus guanidinium, profoundly modulates the hydrophobically driven self-assembly of conformationally stable β-peptides in bulk aqueous solution.

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Section: Discussionmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 76%

Cationic Side Chain Identity Directs the Hydrophobically Driven Self-Assembly of Amphiphilic β-Peptides in Aqueous Solution

et al. 2021

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“…Recent studies have shown that while conservative substitution of LLP2 Arg residues displayed wild-type phenotypes, similar substitution of LLP1 Arg residues resulted in a significant impairment of Env expression, fusogenicity and incorporation, as well as virus replication (Kuhlmann et al, 2014). As shown in Figures 2B and 3E, six arginine residues were concentrated in the polar side of LLP1 which generated a basic surface in the C-terminus of gp41CT C (Figure 3C,E).…”

Section: Resultsmentioning

confidence: 99%

Solution Structure and Membrane Interaction of the Cytoplasmic Tail of HIV-1 gp41 Protein

Samal

Vlach

et al. 2017

Structure

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SUMMARY The cytoplasmic tail of gp41 (gp41CT) remains the last HIV-1 domain with an unknown structure. It plays important roles in HIV-1 replication such as mediating envelope (Env) intracellular trafficking and incorporation into assembling virions, mechanisms of which are poorly understood. Herein, we present the solution structure of gp41CT in a micellar environment and characterize its interaction with the membrane. We show that the N-terminal 45 residues are unstructured and not associated with the membrane. However, the C-terminal 105 residues form three membrane-bound amphipathic a-helices with distinctive structural features such as variable degree of membrane penetration, hydrophobic and basic surfaces, clusters of aromatic residues, and a network of cation-p interactions. This work fills a major gap by providing the structure of the last segment of HIV-1 Env, which will provide insights into the mechanisms of Gag-mediated Env incorporation as well as the overall Env mobility and conformation on the virion surface.

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“…It was reported that mutations of arginine to lysine in the LLP1 motif resulted in significant impairment of Env expression and consequently virus replication kinetics, Env fusogenicity and incorporation. In contrast, Arg-to-Lys substitutions in LLP2 only affected the level of Env incorporation and fusogenicity [157]. Altogether, the structural details on gp41CT [154] have provided insights that may help to understand the mechanisms of Gag-mediated Env incorporation as well as the overall Env mobility and conformation on the virion surface.…”

Section: Structure and Topology Of Gp41ctmentioning

confidence: 98%

The Interplay between HIV-1 Gag Binding to the Plasma Membrane and Env Incorporation

Saad

2020

Viruses

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Advancement in drug therapies and patient care have drastically improved the mortality rates of HIV-1 infected individuals. Many of these therapies were developed or improved upon by using structure-based techniques, which underscore the importance of understanding essential mechanisms in the replication cycle of HIV-1 at the structural level. One such process which remains poorly understood is the incorporation of the envelope glycoprotein (Env) into budding virus particles. Assembly of HIV particles is initiated by targeting of the Gag polyproteins to the inner leaflet of the plasma membrane (PM), a process mediated by the N-terminally myristoylated matrix (MA) domain and phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). There is strong evidence that formation of the Gag lattice on the PM is a prerequisite for the incorporation of Env into budding particles. It is also suggested that Env incorporation is mediated by an interaction between its cytoplasmic tail (gp41CT) and the MA domain of Gag. In this review, we highlight the latest developments and current efforts to understand the interplay between gp41CT, MA, and the membrane during assembly. Elucidation of the molecular determinants of Gag–Env–membrane interactions may help in the development of new antiviral therapeutic agents that inhibit particle assembly, Env incorporation and ultimately virus production.

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Unique Functional Properties of Conserved Arginine Residues in the Lentivirus Lytic Peptide Domains of the C-terminal Tail of HIV-1 gp41

Cited by 9 publications

References 55 publications

Cationic Side Chain Identity Directs the Hydrophobically Driven Self-Assembly of Amphiphilic β-Peptides in Aqueous Solution

Cationic Side Chain Identity Directs the Hydrophobically Driven Self-Assembly of Amphiphilic β-Peptides in Aqueous Solution

Solution Structure and Membrane Interaction of the Cytoplasmic Tail of HIV-1 gp41 Protein

The Interplay between HIV-1 Gag Binding to the Plasma Membrane and Env Incorporation

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