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Brautigam, C.

Publications and source records attributed to Brautigam, C..

2 recordsLinked to original sources
bioRxiv2023

A new Karyopherin-β2 binding PY-NLS epitope of HNRNPH2 is linked to neurodevelopmental disorders

The normally nuclear HNRNPH2 is mutated in HNRNPH2-related X-linked neurodevelopmental disorder causing the protein to accumulate in the cytoplasm. Interactions of HNRNPH2 with its importin Karyopherin-{beta}2 (Transportin-1) had not been studied. We present a structure that shows Karyopherin-{beta}2 binding HNRNPH2 residues 204-215, a proline-tyrosine nuclear localization signal or PY-NLS that contains a typical R-X2-4-P-Y motif, 206RPGPY210, followed a new Karyopherin-{beta}2 binding epitope at 211DRP213 that make many interactions with Karyopherin-{beta}2 W373. Mutations at each of these sites decrease Karyopherin-{beta}2 binding affinities by 70-100 fold, explaining aberrant accumulation in cells and emphasizing the role of nuclear import defects in the disease. Sequence/structure analysis suggests that the new epitope C-terminal of the PY-motif, which binds Karyopherin-{beta}2 W373, is rare and thus far limited to close paralogs HNRNPH2, HNRNPH1 and HNRNPF. Karyopherin-{beta}2 W373, a HNRNPH2-binding hotspot, corresponds to W370 of close paralog Transportin-2, a site of pathological variants in patients with neurodevelopmental abnormalities, suggesting that Transportin-2-HNRNPH2/H1/F interactions may be compromised in the abnormalities. SummaryHNRNPH2 variants in HNRNPH2-related X-linked neurodevelopmental disorder aberrantly accumulate in the cytoplasm. A structure of Karyopherin-{beta}2*HNRNPH2 explains nuclear import defects of the variants, reveals a new NLS epitope that suggests mechanistic changes in pathological variants of Karyopherin-{beta}2 paralog Transportin-2.

biophysics↗
bioRxiv2018

Tv2483, a lipoprotein from Treponema vincentii and homolog of Tp0309 from T. pallidum, is ahighly selective L-arginine-binding protein

Biophysical and biochemical studies on the lipoproteins and other periplasmic proteins from the spirochetal species Treponema pallidum have yielded numerous insights into the functioning of the organisms peculiar membrane organization, its nutritional requirements, and intermediary metabolism. However, not all T. pallidum proteins have proven to be amenable to biophysical studies. One such recalcitrant protein is Tp0309, a putative polar-amino-acid-binding protein of an ABC transporter system. To gain further information on its possible function, a homolog of the protein from the related species T. vincentii was used as a surrogate. This protein, Tv2483, was crystallized, resulting in the determination of its crystal structure at a resolution of 1.75 [A]. The protein has a typical fold for a ligand-binding protein, and a single molecule of L-arginine was bound between its two lobes. Differential scanning fluorimetry and isothermal titration calorimetry experiments confirmed that L-arginine bound to the protein with unusually high selectivity. However, further comparison to Tp0309 showed differences in key amino-acid-binding residues may impart an alternate specificity for the T. pallidum protein.

biophysics↗