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  • 1.
    Carter, Megan
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Jemth, Ann-Sofie
    Carreras-Puigvert, Jordi
    Herr, Patrick
    Martínez Carranza, Markel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Vallin, Karl S. A.
    Throup, Adam
    Helleday, Thomas
    Stenmark, Pål
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Human NUDT22 Is a UDP-Glucose/Galactose Hydrolase Exhibiting a Unique Structural Fold2018In: Structure, ISSN 0969-2126, E-ISSN 1878-4186, Vol. 26, no 2, p. 295-303Article in journal (Refereed)
    Abstract [en]

    Human NUDT22 belongs to the diverse NUDIX family of proteins, but has, until now, remained uncharacterized. Here we show that human NUDT22 is a Mg2+-dependent UDP-glucose and UDP-galactose hydrolase, producing UMP and glucose 1-phosphate or galactose 1-phosphate. We present the structure of human NUDT22 alone and in a complex with the substrate UDP-glucose. These structures reveal a partially conserved NUDIX fold domain preceded by a unique N-terminal domain responsible for UDP moiety binding and recognition. The NUDIX domain of NUDT22 contains a modified NUDIX box identified using structural analysis and confirmed through functional analysis of mutants. Human NUDT22's distinct structure and function as a UDP-carbohydrate hydrolase establish a unique NUDIX protein subfamily.

  • 2.
    Gustafsson, Robert
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Berntsson, Ronnie P-A
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Umeå University, Sweden.
    Martínez-Carranza, Markel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    El Tekle, Geniver
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Odegrip, Richard
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Johnson, Eric A.
    Stenmark, Pål
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Crystal structures of OrfX2 and P47 from a Botulinum neurotoxin OrfX-type gene cluster2017In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 591, no 22, p. 3781-3792Article in journal (Refereed)
    Abstract [en]

    Botulinum neurotoxins are highly toxic substances and are all encoded together with one of two alternative gene clusters, the HA or the OrfX gene cluster. Very little is known about the function and structure of the proteins encoded in the OrfX gene cluster, which in addition to the toxin contains five proteins (OrfX1, OrfX2, OrfX3, P47, and NTNH). We here present the structures of OrfX2 and P47, solved to 2.1 and 1.8 Å, respectively. We show that they belong to the TULIP protein superfamily, which are often involved in lipid binding. OrfX1 and OrfX2 were both found to bind phosphatidylinositol lipids.

  • 3. Götzke, Hansjörg
    et al.
    Kilisch, Markus
    Martínez-Carranza, Markel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Sograte-Idrissi, Shama
    Rajavel, Abirami
    Schlichthaerle, Thomas
    Engels, Niklas
    Jungmann, Ralf
    Stenmark, Pål
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Lund University, Sweden.
    Opazo, Felipe
    Frey, Steffen
    The ALFA-tag is a highly versatile tool for nanobody-based bioscience applications2019In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 4403Article in journal (Refereed)
    Abstract [en]

    Specialized epitope tags are widely used for detecting, manipulating or purifying proteins, but often their versatility is limited. Here, we introduce the ALFA-tag, a rationally designed epitope tag that serves a remarkably broad spectrum of applications in life sciences while outperforming established tags like the HA-, FLAG (R)- or myc-tag. The ALFA-tag forms a small and stable a-helix that is functional irrespective of its position on the target protein in prokaryotic and eukaryotic hosts. We characterize a nanobody (NbALFA) binding ALFA-tagged proteins from native or fixed specimen with low picomolar affinity. It is ideally suited for super-resolution microscopy, immunoprecipitations and Western blotting, and also allows in vivo detection of proteins. We show the crystal structure of the complex that enabled us to design a nanobody mutant (NbALFA(PE)) that permits efficient one-step purifications of native ALFA-tagged proteins, complexes and even entire living cells using peptide elution under physiological conditions.

  • 4.
    Martínez-Carranza, Markel
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Blasco, Pilar
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Gustafsson, Robert
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Dong, Min
    Berntsson, Ronnie Per-Arne
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Stenmark, Pål
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Lund University, Sweden.
    Synaptotagmin Binding to Botulinum Neurotoxins2020In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 59, no 4, p. 491-498Article in journal (Refereed)
    Abstract [en]

    Botulinum neurotoxins (BoNTs) are exceptionally toxic proteins that cause paralysis but are also extensively used as treatment for various medical conditions. Most BoNTs bind two receptors on neuronal cells, namely, a ganglioside and a protein receptor. Differences in the sequence between the protein receptors from different species can impact the binding affinity and toxicity of the BoNTs. Here we have investigated how BoNT/B, /DC, and /G, all three toxins that utilize synaptotagmin I and II (Syt-I and Syt-II, respectively) as their protein receptors, bind to Syt-I and -II of mouse/rat, bovine, and human origin by isothermal titration calorimetry analysis. BoNT/G had the highest affinity for human Syt-I, and BoNT/DC had the highest affinity for bovine Syt-II. As expected, BoNT/B, /DC, and /G showed very low levels of binding to human Syt-II. Furthermore, we carried out saturation transfer difference (STD) and STD-TOCSY NMR experiments that revealed the region of the Syt peptide in direct contact with BoNT/G, which demonstrate that BoNT/G recognizes the Syt peptide in a model similar to that in the established BoNT/B-Syt-II complex. Our analyses also revealed that regions outside the Syt peptide’s toxin-binding region are important for the helicity of the peptide and, therefore, the binding affinity.

  • 5.
    Martínez-Carranza, Markel
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Škerlová, Jana
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Henriksson, Linda
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Stenmark, Pål
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Structure and pH stability of botulinum neurotoxin X in complex with NTNHManuscript (preprint) (Other academic)
    Abstract [en]

    Botulinum neurotoxins (BoNTs) are the most potent toxins known to man and are also used to treat an increasing number of medical disorders. They target the neuromuscular junction and inhibit synaptic vesicle exocytosis in motor neurons, thereby causing paralysis. The molecular architecture of BoNTs comprises the receptor-binding domain, translocation domain, and zinc dependent protease domain. BoNTs are naturally co-expressed with a non-toxic non-hemagglutinin partner (NTNH) with which they form the minimal progenitor toxin complex to resist the low pH and proteases in the intestine, before they cross the intestinal barrier in the host. The full-length structures of BoNT/A, BoNT/B and BoNT/E have been determined and the structures of minimal progenitor toxin complexes of BoNT/A and BoNT/E are also available.

    We have recently identified and characterized a new botulinum neurotoxin serotype, BoNT/X. It shares the lowest sequence identity with other BoNTs and is not recognized by antisera against known BoNTs. BoNT/X cleaves its substrates at a novel site and is the only BoNT that also cleaves other non-canonical substrates. The only structural information currently available for this novel toxin is the structure of its protease domain (light chain).

    We have determined the structure of the 300 kDa BoNT/X-NTNH complex at 3.12 Å resolution using single-particle cryo-electron microscopy. This structure together with the pH stability analysis of the complex provides the molecular basis to understand the toxin’s interactions with its protective partner and also the evolutionary relationships between BoNT serotypes.

  • 6.
    Notari, Luigi
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Martínez-Carranza, Markel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Farías-Rico, José Arcadio
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Stenmark, Pål
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Cotranslational Folding of a Pentarepeat beta-Helix Protein2018In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 430, no 24, p. 5196-5206Article in journal (Refereed)
    Abstract [en]

    It is becoming increasingly clear that many proteins start to fold cotranslationally before the entire polypeptide chain has been synthesized on the ribosome. One class of proteins that a priori would seem particularly prone to cotranslational folding is repeat proteins, that is, proteins that are built from an array of nearly identical sequence repeats. However, while the folding of repeat proteins has been studied extensively in vitro with purified proteins, only a handful of studies have addressed the issue of cotranslational folding of repeat proteins. Here, we have determined the structure and studied the cotranslational folding of a beta-helix pentarepeat protein from the human pathogen Clostridium botulinum a homolog of the fluoroquinolone resistance protein MfpA-using an assay in which the SecM translational arrest peptide serves as a force sensor to detect folding events. We find that cotranslational folding of a segment corresponding to the first four of the eight beta-helix coils in the protein produces enough force to release ribosome stalling and that folding starts when this unit is similar to 35 residues away from the P-site, near the distal end of the ribosome exit tunnel. An additional folding transition is seen when the whole PENT moiety emerges from the exit tunnel. The early cotranslational formation of a folded unit may be important to avoid misfolding events in vivo and may reflect the minimal size of a stable beta-helix since it is structurally homologous to the smallest known beta-helix protein, a four-coil protein that is stable in solution.

  • 7. Zhang, Sicai
    et al.
    Lebreton, Francois
    Mansfield, Michael J.
    Miyashita, Shin-Ichiro
    Zhang, Jie
    Schwartzman, Julia A.
    Tao, Liang
    Masuyer, Geoffrey
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Martínez-Carranza, Markel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Stenmark, Pål
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gilmore, Michael S.
    Doxey, Andrew C.
    Dong, Min
    Identification of a Botulinum Neurotoxin-like Toxin in a Commensal Strain of Enterococcus faecium2018In: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 23, no 2, p. 169-176Article in journal (Refereed)
    Abstract [en]

    Botulinumneurotoxins (BoNTs), produced by various Clostridium strains, are a family of potent bacterial toxins and potential bioterrorism agents. Here we report that an Enterococcus faecium strain isolated from cow feces carries a BoNT-like toxin, designated BoNT/En. It cleaves both VAMP2 and SNAP-25, proteins that mediate synaptic vesicle exocytosis in neurons, at sites distinct from known BoNT cleavage sites on these two proteins. Comparative genomic analysis determines that the E. faecium strain carrying BoNT/En is a commensal type and that the BoNT/En gene is located within a typical BoNT gene cluster on a 206 kb putatively conjugative plasmid. Although the host species targeted by BoNT/En remains to be determined, these findings establish an extended member of BoNTs and demonstrate the capability of E. faecium, a commensal organism ubiquitous in humans and animals and a leading cause of hospital-acquired multi-drug-resistant (MDR) infections, to horizontally acquire, and possibly disseminate, a unique BoNT gene cluster.

  • 8. Zhang, Sicai
    et al.
    Masuyer, Geoffrey
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Zhang, Jie
    Shen, Yi
    Lundin, Daniel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Henriksson, Linda
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Miyashita, Shin-Ichiro
    Martínez-Carranza, Markel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Dong, Min
    Stenmark, Pål
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Identification and characterization of a novel botulinum neurotoxin2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 14130Article in journal (Refereed)
    Abstract [en]

    Botulinum neurotoxins are known to have seven serotypes (BoNT/A-G). Here we report a new BoNT serotype, tentatively named BoNT/X, which has the lowest sequence identity with other BoNTs and is not recognized by antisera against known BoNTs. Similar to BoNT/B/D/F/G, BoNT/X cleaves vesicle-associated membrane proteins (VAMP) 1, 2 and 3, but at a novel site (Arg66-Ala67 in VAMP2). Remarkably, BoNT/X is the only toxin that also cleaves non-canonical substrates VAMP4, VAMP5 and Ykt6. To validate its activity, a small amount of full-length BoNT/X was assembled by linking two non-toxic fragments using a transpeptidase (sortase). Assembled BoNT/X cleaves VAMP2 and VAMP4 in cultured neurons and causes flaccid paralysis in mice. Thus, BoNT/X is a novel BoNT with a unique substrate profile. Its discovery posts a challenge to develop effective countermeasures, provides a novel tool for studying intracellular membrane trafficking, and presents a new potential therapeutic toxin for modulating secretions in cells.

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