Asp22 drives the protonation state of the Staphylococcus epidermidis glucose/H+ symporter

Seica, Ana Filipa Santos; Iancu, Cristina V.; Pfeilschifter, Benedikt; Madej, M. Gregor; Choe, Juhui; Hellwig, Petra

doi:10.1074/jbc.ra120.014069

Cited by 4 publications

(5 citation statements)

References 45 publications

(122 reference statements)

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“…Consistently, an Asp27Asn mutant in XylE and an Asp22Asn mutant in GlcP Se binds d -xylose and d -glucose with the same affinity as wild-type, respectively. 34 , 273 The structure of the H + -coupled glucose symporter STP10 was determined from crystals grown at low pH. 234 At low pH, the equivalent aspartate (Asp42) is thought to be in the protonated state and no longer forming a salt bridge to the equivalent arginine (Arg142), and TM1 has moved in toward the bound d -glucose ( Figure 14 a).…”

Section: The Alternating-access Mechanism Of Glucose (Glut) Transportmentioning

confidence: 99%

Structures and General Transport Mechanisms by the Major Facilitator Superfamily (MFS)

et al. 2021

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The major facilitator superfamily (MFS) is the largest known superfamily of secondary active transporters. MFS transporters are responsible for transporting a broad spectrum of substrates, either down their concentration gradient or uphill using the energy stored in the electrochemical gradients. Over the last 10 years, more than a hundred different MFS transporter structures covering close to 40 members have provided an atomic framework for piecing together the molecular basis of their transport cycles. Here, we summarize the remarkable promiscuity of MFS members in terms of substrate recognition and proton coupling as well as the intricate gating mechanisms undergone in achieving substrate translocation. We outline studies that show how residues far from the substrate binding site can be just as important for fine-tuning substrate recognition and specificity as those residues directly coordinating the substrate, and how a number of MFS transporters have evolved to form unique complexes with chaperone and signaling functions. Through a deeper mechanistic description of glucose (GLUT) transporters and multidrug resistance (MDR) antiporters, we outline novel refinements to the rocker-switch alternating-access model, such as a latch mechanism for proton-coupled monosaccharide transport. We emphasize that a full understanding of transport requires an elucidation of MFS transporter dynamics, energy landscapes, and the determination of how rate transitions are modulated by lipids.

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Section: The Alternating-access Mechanism Of Glucose (Glut) Transportmentioning

confidence: 99%

Structures and General Transport Mechanisms by the Major Facilitator Superfamily (MFS)

et al. 2021

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“…Having characterized the aspects of the sugar porter transport cycle that are likely conserved across the family, we turn to family-specific features, with a focus on the differences between passive and proton-coupled transporters, such as XylE. The current working model is that an aspartic acid reside in TM1 (Asp27 in XylE) is allosterically coupled to the sugar transport but does not participate directly in sugar binding ( Drew et al, 2021 ; Ke et al, 2017 ; Seica et al, 2020 ; Jia et al, 2020 ). Indeed, the aspartic acid to asparagine mutant has the same sugar-binding affinity as wild type ( Madej et al, 2014 ).…”

Section: Resultsmentioning

confidence: 99%

Reconstructing the transport cycle in the sugar porter superfamily using coevolution-powered machine learning

Mitrovic

McComas

Alleva

et al. 2023

eLife

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Sugar porters (SPs) represent the largest group of secondary-active transporters. Some members, such as the glucose transporters (GLUTs), are well known for their role in maintaining blood glucose homeostasis in mammals, with their expression upregulated in many types of cancers. Because only a few sugar porter structures have been determined, mechanistic models have been constructed by piecing together structural states of distantly related proteins. Current GLUT transport models are predominantly descriptive and oversimplified. Here, we have combined coevolution analysis and comparative modeling, to predict structures of the entire sugar porter superfamily in each state of the transport cycle. We have analyzed the state-specific contacts inferred from coevolving residue pairs and shown how this information can be used to rapidly generate free-energy landscapes consistent with experimental estimates, as illustrated here for the mammalian fructose transporter GLUT5. By comparing many different sugar porter models and scrutinizing their sequence, we have been able to define the molecular determinants of the transport cycle, which are conserved throughout the sugar porter superfamily. We have also been able to highlight differences leading to the emergence of proton-coupling, validating, and extending the previously proposed latch mechanism. Our computational approach is transferable to any transporter, and to other protein families in general.

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“…Having characterized the aspects of the sugar porter transport cycle that are likely conserved across the family, we turn to family-specific features, with a focus on the differences between passive and proton-coupled transporters, such as XylE. The current working model is that an aspartic acid reside in TM1 (Asp27 in XylE) is allosterically coupled to the sugar transport, but does not participate directly in sugar binding 2,36,48,49 .…”

Section: Coevolving Residues Support Proton-coupling In Sugar Portersmentioning

confidence: 99%

Reconstructing the transport cycle in the sugar porter superfamily using coevolution-powered machine learning

Mitrovic

McComas

Alleva

et al. 2022

Preprint

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Sugar porters represent the largest group of secondary-active transporters. Some members, such as the glucose (GLUT) transporters, are well-known for their role in maintaining blood glucose homeostasis in mammals, with their expression upregulated in many types of cancers. Because only a few sugar porter structures have been determined, mechanistic models have been constructed by piecing together structural states of distantly-related proteins. Current GLUT transport models are predominantly descriptive, and oversimplified. Here, we have combined coevolution analysis and comparative modeling, to predict structures of the entire sugar porter superfamily in each state of the transport cycle. We have analysed the state-specific contacts inferred from coevolving residue pairs, and shown how this information can be used to rapidly generate free-energy landscapes consistent with experimental estimates, as illustrated here for the mammalian fructose transporter GLUT5. By comparing many different sugar porter models and scrutinizing their sequence, we have been able to define the molecular determinants of the transport cycle, which are conserved throughout the sugar porter superfamily. We have also been able to highlight differences leading to the emergence of proton-coupling, validating and extending the previously proposed latch mechanism. Our computational approach is transferable to any transporter, and to other protein families in general.

show abstract

Asp22 drives the protonation state of the Staphylococcus epidermidis glucose/H+ symporter

Cited by 4 publications

References 45 publications

Structures and General Transport Mechanisms by the Major Facilitator Superfamily (MFS)

Structures and General Transport Mechanisms by the Major Facilitator Superfamily (MFS)

Reconstructing the transport cycle in the sugar porter superfamily using coevolution-powered machine learning

Reconstructing the transport cycle in the sugar porter superfamily using coevolution-powered machine learning

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