A blueprint for robust crosslinking of mobile species in biogels with weakly adhesive molecular anchors

Newby, Jay M.; Schiller, Jennifer L.; Wessler, Timothy; Edelstein, Jasmine; Forest, M. Gregory; Lai, Samuel K.

doi:10.1038/s41467-017-00739-6

Cited by 32 publications

(47 citation statements)

References 28 publications

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“…In this paper, we propose a new theory (which is not mutually exclusive to those previously proposed), namely, that limited processivity can improve the overall flux of cargoes when cargoes and motors must first diffusively self assemble into complexes before engaging in active transport. Our conclusions are motivated by a recent theory for how antibodies trap virus in mucosal barriers by accumulating multiple antibodies on the viral surface that crosslink it to elements of the mucus polymer network [12]. Our analysis shows that the improvement of cargo transport flux from lowering motor processivity is due to several competing factors.…”

Section: Introductionmentioning

confidence: 89%

Limited processivity of single motors improves overall transport flux of self-assembled motor-cargo complexes

et al. 2019

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Single kinesin molecular motors can processively move along a microtubule (MT) a few micrometers on average before dissociating. However, cellular length scales over which transport occurs are several hundred microns and more. Why seemingly unreliable motors are used to transport cellular cargo remains poorly understood. We propose a new theory for how low processivity, the average length of a single bout of directed motion, can enhance cellular transport when motors and cargoes must first diffusively self assemble into complexes. We employ stochastic modeling to determine the effect of processivity on overall cargo transport flux. We show that, under a wide range of physiologically relevant conditions, possessing "infinite" processivity does not maximize flux along MTs. Rather, we find that low processivity i.e., weak binding of motors to MTs, is optimal. These results shed light on the relationship between processivity and transport efficiency and offer a new theory for the physiological benefits of low motor processivity.

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Section: Introductionmentioning

confidence: 89%

Limited processivity of single motors improves overall transport flux of self-assembled motor-cargo complexes

et al. 2019

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“…Such modestly slowed diffusion is consistent with antibodies making weak and transient bonds with the mucins. In turn, the weak affinity of individual antibody–mucin bonds allow individual antibodies to diffuse rapidly within the mucus gel, thereby enabling them to contact and coat the surfaces of pathogens or sperm to which they bind specifically [ 24 , 25 ]. As the antibodies assemble on the surface of sperm (or pathogens), they form an array of Fc moieties that can make multiple low-affinity bonds to the mucus gel.…”

Section: Functions Of Antisperm Antibodies That Can Affect Fertilitymentioning

confidence: 99%

Engineering monoclonal antibody-based contraception and multipurpose prevention technologies†

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et al. 2020

Biology of Reproduction

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Abstract Sexually transmitted infections are highly prevalent, and over 40% of pregnancies are unplanned. We are producing new antibody-based multipurpose prevention technology products to address these problems and fill an unmet need in female reproductive health. We used a Nicotiana platform to manufacture monoclonal antibodies against two prevalent sexually transmitted pathogens, HIV-1 and HSV-2, and incorporated them into a vaginal film (MB66) for preclinical and Phase 1 clinical testing. These tests are now complete and indicate that MB66 is effective and safe in women. We are now developing an antisperm monoclonal antibody to add contraceptive efficacy to this product. The antisperm antibody, H6-3C4, originally isolated by Shinzo Isojima from the blood of an infertile woman, recognizes a carbohydrate epitope on CD52g, a glycosylphosphatidylinositol-anchored glycoprotein found in abundance on the surface of human sperm. We engineered the antibody for production in Nicotiana; the new antibody which we call “human contraception antibody,” effectively agglutinates sperm at concentrations >10 μg/ml and maintains activity under a variety of physiological conditions. We are currently seeking regulatory approval for a Phase 1 clinical trial, which will include safety and “proof of principle” efficacy endpoints. Concurrently, we are working with new antibody production platforms to bring the costs down, innovative antibody designs that may produce more effective second-generation antibodies, and delivery systems to provide extended protection.

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“…In the following, we consider both models of cooperative cargo transport with identical motors (Klumpp and Lipowsky 2005;Kunwar and Mogilner 2010) and tug-of-war models of bidirectional transport driven by identical or different motors moving in opposite directions (Müller et al 2008(Müller et al , 2010. While not discussed here, this framework may also prove useful in analyzing stochastic models of nanoparticulate transport in biogels, where states correspond to the number of occupied binding sites on nanoparticulates and to the number of molecular anchors crosslinking them to the matrix of polymers (Newby et al 2017).…”

Section: Application To Cooperative and Tug-of-war Models Of Cargo Trmentioning

confidence: 99%

Renewal Reward Perspective on Linear Switching Diffusion Systems in Models of Intracellular Transport

et al. 2020

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In many biological systems, the movement of individual agents is characterized having multiple qualitatively distinct behaviors that arise from a variety of biophysical states. For example, in cells the movement of vesicles, organelles, and other intracellular cargo is affected by their binding to and unbinding from cytoskeletal filaments such as microtubules through molecular motor proteins. A typical goal of theoretical or numerical analysis of models of such systems is to investigate effective transport properties and their dependence on model parameters. While the effective velocity of particles undergoing switching diffusion dynamics is often easily characterized in terms of the long-time fraction of time that particles spend in each state, the calculation of the effective diffusivity is more complicated because it cannot be expressed simply in terms of a statistical average of the particle transport state at one moment of time. However, it is common that these systems are regenerative, in the sense that they can be decomposed into independent cycles marked by returns to a base state. Using decompositions of this kind, we calculate effective transport properties by computing the moments of the dynamics within each cycle and then applying renewal reward theory. This method provides a useful alternative large-time analysis to direct homogenization for linear advection–reaction–diffusion partial differential equation models. Moreover, it applies to a general class of semi-Markov processes and certain stochastic differential equations that arise in models of intracellular transport. Applications of the proposed renewal reward framework are illustrated for several case studies such as mRNA transport in developing oocytes and processive cargo movement by teams of molecular motor proteins.

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A blueprint for robust crosslinking of mobile species in biogels with weakly adhesive molecular anchors

Cited by 32 publications

References 28 publications

Limited processivity of single motors improves overall transport flux of self-assembled motor-cargo complexes

Limited processivity of single motors improves overall transport flux of self-assembled motor-cargo complexes

Engineering monoclonal antibody-based contraception and multipurpose prevention technologies†

Renewal Reward Perspective on Linear Switching Diffusion Systems in Models of Intracellular Transport

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