Sarah E. van Rossum-Fikkert

Bio: Sarah E. van Rossum-Fikkert is an academic researcher from Erasmus University Rotterdam. The author has contributed to research in topics: Homologous recombination & DNA repair. The author has an hindex of 10, co-authored 11 publications receiving 1510 citations. Previous affiliations of Sarah E. van Rossum-Fikkert include Netherlands Cancer Institute.

Crystal structure of nicotinic acetylcholine receptor homolog AChBP in complex with an alpha-conotoxin PnIA variant.

Abstract: Conotoxins (Ctx) form a large family of peptide toxins from cone snail venoms that act on a broad spectrum of ion channels and receptors. The subgroup alpha-Ctx specifically and selectively binds to subtypes of nicotinic acetylcholine receptors (nAChRs), which are targets for treatment of several neurological disorders. Here we present the structure at a resolution of 2.4 A of alpha-Ctx PnIA (A10L D14K), a potent blocker of the alpha(7)-nAChR, bound with high affinity to acetylcholine binding protein (AChBP), the prototype for the ligand-binding domains of the nAChR superfamily. Alpha-Ctx is buried deep within the ligand-binding site and interacts with residues on both faces of adjacent subunits. The toxin itself does not change conformation, but displaces the C loop of AChBP and induces a rigid-body subunit movement. Knowledge of these contacts could facilitate the rational design of drug leads using the Ctx framework and may lead to compounds with increased receptor subtype selectivity.

Functional characterization of Rad18 domains for Rad6, ubiquitin, DNA binding and PCNA modification

Abstract: Rad18 is a ubiquitin E3 ligase that monoubiquitinates PCNA on stalled replications forks. This allows recruitment of damage-tolerant polymerases for damage bypass and DNA repair. In this activity, the Rad18 protein has to interact with Rad6, the E2 ubiquitin-conjugating enzyme, ubiquitin, PCNA and DNA. Here we analyze the biochemical interactions of specific domains of the Rad18 protein. We found that the Rad6/Rad18 complex forms stable dimers in vitro. Consistent with previous findings, both the Ring domain and a C-terminal region contribute to the Rad6 interaction, while the C-terminus is not required for the interaction with PCNA. Surprisingly we find that the C2HC zinc finger is important for interaction with ubiquitin, apparently analogous to the interactions of classical zinc fingers with ubiquitin such as found in the UBZ and UBM domains in Y-family polymerases. Finally we find that the SAP domain, but not the zinc finger domain, is capable of DNA binding in vitro.

Cho, a second endonuclease involved in Escherichia coli nucleotide excision repair.

Abstract: Nucleotide excision repair removes damages from the DNA by incising the damaged strand on the 3' and 5' sides of the lesion. In Escherichia coli, the two incisions are made by the UvrC protein, which consists of two functional halves. The N-terminal half contains the catalytic site for 3' incision and the C-terminal half contains the residues involved in 5' incision. The genome of E. coli contains an SOS-inducible gene (ydjQ) encoding a protein that is homologous to the N-terminal half of UvrC. In this paper we show that this protein, which we refer to as Cho (UvrC homologue), can incise the DNA at the 3' side of a lesion during nucleotide excision repair. The incision site of Cho is located 4 nt further away from the damage compared with the 3' incision site of UvrC. Cho and UvrC bind to different domains of UvrB, which is probably the reason of the shift in incision position. Some damaged substrates that are poorly incised by UvrC are very efficiently incised by Cho. We propose that E. coli uses Cho for repair of such damages in vivo. Initially, most of the lesions in the cell will be repaired by the action of UvrC alone. Remaining damages, that for structural reasons obstruct the 3' incision by UvrC, will be repaired by the combined action of Cho (for 3' incision) and UvrC (for 5' incision).

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

“Bioinformatics” 특집을 내면서

Abstract: BIOE 402. Medical Technology Assessment. 2 or 3 hours. Bioentrepreneur course. Assessment of medical technology in the context of commercialization. Objectives, competition, market share, funding, pricing, manufacturing, growth, and intellectual property; many issues unique to biomedical products. Course Information: 2 undergraduate hours. 3 graduate hours. Prerequisite(s): Junior standing or above and consent of the instructor.

RING Domain E3 Ubiquitin Ligases

Abstract: E3 ligases confer specificity to ubiquitination by recognizing target substrates and mediating transfer of ubiquitin from an E2 ubiquitinconjugating enzyme to substrate. The activity of most E3s is specified by a RING domain, which binds to an E2∼ubiquitin thioester and activates discharge of its ubiquitin cargo. E2-E3 complexes can either monoubiquitinate a substrate lysine or synthesize polyubiquitin chains assembled via different lysine residues of ubiquitin. These modifications can have diverse effects on the substrate, ranging from proteasome-dependent proteolysis to modulation of protein function, structure, assembly, and/or localization. Not surprisingly, RING E3mediated ubiquitination can be regulated in a number of ways. RING-based E3s are specified by over 600 human genes, surpassing the 518 protein kinase genes. Accordingly, RING E3s have been linked to the control of many cellular processes and to multiple human diseases. Despite their critical importance, our knowledge of the physiological partners, biological functions, substrates, and mechanism of action for most RING E3s remains at a rudimentary stage.

Mammalian nicotinic acetylcholine receptors: from structure to function.

Abstract: The classical studies of nicotine by Langley at the turn of the 20th century introduced the concept of a “receptive substance,” from which the idea of a “receptor” came to light. Subsequent studies...