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。

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

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Principles Of Fluorescence Spectroscopy

The Hsp70 and Hsp60 chaperone machines.

Since the discovery of SNARE proteins in the late 1980s, SNAREs have been recognized as key components of protein complexes that drive membrane fusion. Despite considerable sequence divergence among SNARE proteins, their mechanism seems to be conserved and is adaptable for fusion reactions as diverse as those involved in cell growth, membrane repair, cytokinesis and synaptic transmission. A fascinating picture of these robust nanomachines is emerging.

/pdf/snares-engines-for-membrane-fusion-dircca11bk.pdf

SNAREs--engines for membrane fusion.

T URNOVER OF AB ERR ANT PROT EINS IN E. COLI . . . . . . . . . . . . . . . . . 445 The Lon Protease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446 DnaK. DnaJ. GrpE. GroEL and GroES . . . . . . . . . . . . . . . . . . . . . . . . . . 447 The Clp Protease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448 The DegP Protease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 452

The Function of Heat-Shock Proteins in Stress Tolerance: Degradation and Reactivation of Damaged Proteins

Protein–protein interactions can be designed computationally by using positive strategies that maximize the stability of the desired structure and/or by negative strategies that seek to destabilize competing states. Here, we compare the efficacy of these methods in reengineering a protein homodimer into a heterodimer. The stability-design protein (positive design only) was experimentally more stable than the specificity-design heterodimer (positive and negative design). By contrast, only the specificity-design protein assembled as a homogenous heterodimer in solution, whereas the stability-design protein formed a mixture of homodimer and heterodimer species. The experimental stabilities of the engineered proteins correlated roughly with their calculated stabilities, and the crystal structure of the specificity-design heterodimer showed most of the predicted side-chain packing interactions and a main-chain conformation indistinguishable from the wild-type structure. These results indicate that the design simulations capture important features of both stability and structure and demonstrate that negative design can be critical for attaining specificity when competing states are close in structure space.

https://www.pnas.org/content/pnas/102/36/12724.full.pdf

Specificity versus stability in computational protein design

ClpXP is an ATP‐dependent protease that denatures native proteins and translocates the denatured polypeptide into an interior peptidase chamber for degradation. To address the mechanism of these processes, Arc repressor variants with dramatically different stabilities and unfolding half‐lives varying from months to seconds were targeted to ClpXP by addition of the ssrA degradation tag. Remarkably, ClpXP degraded each variant at a very similar rate and hydrolyzed ∼150 molecules of ATP for each molecule of substrate degraded. The hyperstable substrates did, however, slow the ClpXP ATPase cycle. These results confirm that ClpXP uses an active mechanism to denature its substrates, probably one that applies mechanical force to the native structure. Furthermore, the data suggest that denaturation is inherently inefficient or that significant levels of ATP hydrolysis are required for other reaction steps. ClpXP degraded disulfide‐cross‐linked dimers efficiently, even when just one subunit contained an ssrA tag. This result indicates that the pore through which denatured proteins enter the proteolytic chamber must be large enough to accommodate simultaneous passage of two or three polypeptide chains.

/pdf/effects-of-protein-stability-and-structure-on-substrate-3i8dn2rc9j.pdf

Effects of protein stability and structure on substrate processing by the ClpXP unfolding and degradation machine

The Escherichia coli initiator protein, dnaA complexed with ATP, binds to the replication origin (oriC) and melts the duplex in the AT-rich part of oriC. Opening of the duplex requires a minimum temperature and superhelix density. A low level of HU protein (5 molecules/oriC) is stimulatory, probably by facilitating DNA bending. High levels of HU protein (136 molecules/oriC) restrain the free superhelicity. Under adverse conditions for oriC melting (i.e. absence of HU, high levels of HU, low temperature or low superhelicity), transcription can activate initiation of replication by generating an R-loop located even a large distance from oriC. The strand-separation stage at oriC prior to the entry of the dnaB helicase was specifically stimulated. Activation by the R-loop was blocked when a stretch of 14 GC base pairs was inserted between the loop and oriC. Thus, activation of oriC by the distantly located R-loop appears to require propagation of DNA melting through the intervening sequence.

Strand separation required for initiation of replication at the chromosomal origin of E.coli is facilitated by a distant RNA-DNA hybrid

In the ClpXP compartmental protease, ring hexamers of the AAA(+) ClpX ATPase bind, denature and then translocate protein substrates into the degradation chamber of the double-ring ClpP(14) peptidase. A key question is the extent to which functional communication between ClpX and ClpP occurs and is regulated during substrate processing. Here, we show that ClpX-ClpP affinity varies with the protein-processing task of ClpX and with the catalytic engagement of the active sites of ClpP. Functional communication between symmetry-mismatched ClpXP rings depends on the ATPase activity of ClpX and seems to be transmitted through structural changes in its IGF loops, which contact ClpP. A conserved arginine in the sensor II helix of ClpX links the nucleotide state of ClpX to the binding of ClpP and protein substrates. A simple model explains the observed relationships between ATP binding, ATP hydrolysis and functional interactions between ClpX, protein substrates and ClpP.

/pdf/communication-between-clpx-and-clpp-during-substrate-14wje8t2sk.pdf

Tania A. Baker

Papers

Specificity versus stability in computational protein design

Effects of protein stability and structure on substrate processing by the ClpXP unfolding and degradation machine

Strand separation required for initiation of replication at the chromosomal origin of E.coli is facilitated by a distant RNA-DNA hybrid

Communication between ClpX and ClpP during substrate processing and degradation

Distinct static and dynamic interactions control ATPase-peptidase communication in a AAA+ protease.