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Article ; Online: Spatial Control of Biochemical Modification Cascades and Pathways.

Alam-Nazki, Aiman / Krishnan, J

2015 Volume 108, Issue 12, Page(s) 2912–2924

Abstract: Information transmission in cells occurs through complex networks of proteins and genes and is relayed through cascades of biochemical modifications, which are typically studied through ordinary differential equations. However, it is becoming ... ...

Abstract	Information transmission in cells occurs through complex networks of proteins and genes and is relayed through cascades of biochemical modifications, which are typically studied through ordinary differential equations. However, it is becoming increasingly clear that spatial factors can strongly influence chemical information transmission in cells. In this article, we systematically disentangle the effects of space in signaling cascades. This is done by examining the effects of localization/compartmentalization and diffusion of enzymes and substrates in multiple variants of chemical modification cascades. This includes situations where the modified form of species at one stage 1) acts as an enzyme for the next stage; 2) acts as a substrate for the next stage; and 3) is involved in phosphotransfer. Our analysis reveals the multiple effects of space in signal transduction cascades. Although in some cases space plays a modulatory effect (itself of interest), in other cases, spatial regulation and control can profoundly affect the nature of information processing as a result of the subtle interplay between the patterns of localization of species, diffusion, and the nature of the modification cascades. Our results provide a platform for disentangling the role of space and spatial control in multiple cellular contexts and a basis for engineering spatial control in signaling cascades through localization/compartmentalization.
MeSH term(s)	Cell Compartmentation ; Metabolome ; Models, Theoretical ; Protein Processing, Post-Translational ; Signal Transduction
Language	English
Publishing date	2015-06-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2015.05.012
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Article ; Online: Covalent modification cycles through the spatial prism.

Alam-Nazki, Aiman / Krishnan, J

Biophysical journal

2013 Volume 105, Issue 7, Page(s) 1720–1731

Abstract: Covalent modification cycles are basic units and building blocks of posttranslational modification and cellular signal transduction. We systematically explore different spatial aspects of signal transduction in covalent modification cycles by starting ... ...

Abstract	Covalent modification cycles are basic units and building blocks of posttranslational modification and cellular signal transduction. We systematically explore different spatial aspects of signal transduction in covalent modification cycles by starting with a basic temporal cycle as a reference and focusing on steady-state signal transduction. We consider, in turn, the effect of diffusion on spatial signal transduction, spatial analogs of ultrasensitive behavior, and the interplay between enzyme localization and substrate diffusion. Our analysis reveals the need to explicitly account for kinetics and diffusional transport (and localization) of enzymes, substrates, and complexes. It demonstrates a complex and subtle interplay between spatial heterogeneity, diffusion, and localization. Overall, examining the spatial dimension of covalent modification reveals that 1), there are important differences between spatial and temporal signal transduction even in this cycle; and 2), spatial aspects may play a substantial role in affecting and distorting information transfer in modules/networks that are usually studied in purely temporal terms. This has important implications for the systematic understanding of signaling in covalent modification cycles, pathways, and networks in multiple cellular contexts.
MeSH term(s)	Diffusion ; Enzymes/metabolism ; Kinetics ; Models, Biological ; Protein Processing, Post-Translational ; Signal Transduction ; Substrate Cycling
Chemical Substances	Enzymes
Language	English
Publishing date	2013-08-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2013.06.050
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Article ; Online: An investigation of spatial signal transduction in cellular networks.

Alam-Nazki, Aiman / Krishnan, J

BMC systems biology

2012 Volume 6, Page(s) 83

Abstract: Background: Spatial signal transduction plays a vital role in many intracellular processes such as eukaryotic chemotaxis, polarity generation and cell division. Furthermore it is being increasingly realized that the spatial dimension to signalling may ... ...

Abstract	Background: Spatial signal transduction plays a vital role in many intracellular processes such as eukaryotic chemotaxis, polarity generation and cell division. Furthermore it is being increasingly realized that the spatial dimension to signalling may play an important role in other apparently purely temporal signal transduction processes. It is increasingly being recognized that a conceptual basis for studying spatial signal transduction in signalling networks is necessary. Results: In this work we examine spatial signal transduction in a series of standard motifs/networks. These networks include coherent and incoherent feedforward, positive and negative feedback, cyclic motifs, monostable switches, bistable switches and negative feedback oscillators. In all these cases, the driving signal has spatial variation. For each network we consider two cases, one where all elements are essentially non-diffusible, and the other where one of the network elements may be highly diffusible. A careful analysis of steady state signal transduction provides many insights into the behaviour of all these modules. While in the non-diffusible case for the most part, spatial signalling reflects the temporal signalling behaviour, in the diffusible cases, we see significant differences between spatial and temporal signalling characteristics. Our results demonstrate that the presence of diffusible elements in the networks provides important constraints and capabilities for signalling. Conclusions: Our results provide a systematic basis for understanding spatial signalling in networks and the role of diffusible elements therein. This provides many insights into the signal transduction capabilities and constraints in such networks and suggests ways in which cellular signalling and information processing is organized to conform to or bypass those constraints. It also provides a framework for starting to understand the organization and regulation of spatial signal transduction in individual processes.
MeSH term(s)	Cells/cytology ; Diffusion ; Feedback, Physiological ; Models, Biological ; Signal Transduction ; Systems Biology/methods
Language	English
Publishing date	2012-07-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1752-0509
ISSN (online)	1752-0509
DOI	10.1186/1752-0509-6-83
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Article ; Online: The interplay of spatial organization and biochemistry in building blocks of cellular signalling pathways.

Krishnan, J / Lu, Lingjun / Alam Nazki, Aiman

Journal of the Royal Society, Interface

2020 Volume 17, Issue 166, Page(s) 20200251

Abstract: Biochemical pathways and networks are central to cellular information processing. While a broad range of studies have dissected multiple aspects of information processing in biochemical pathways, the effect of spatial organization remains much less ... ...

Abstract	Biochemical pathways and networks are central to cellular information processing. While a broad range of studies have dissected multiple aspects of information processing in biochemical pathways, the effect of spatial organization remains much less understood. It is clear that space is central to intracellular organization, plays important roles in cellular information processing and has been exploited in evolution; additionally, it is being increasingly exploited in synthetic biology through the development of artificial compartments, in a variety of ways. In this paper, we dissect different aspects of the interplay between spatial organization and biochemical pathways, by focusing on basic building blocks of these pathways: covalent modification cycles and two-component systems, with enzymes which may be monofunctional or bifunctional. Our analysis of spatial organization is performed by examining a range of 'spatial designs': patterns of localization or non-localization of enzymes/substrates, theoretically and computationally. Using these well-characterized
MeSH term(s)	Biochemistry ; Computer Simulation ; Kinetics ; Synthetic Biology
Language	English
Publishing date	2020-05-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2156283-0
ISSN	1742-5662 ; 1742-5689
ISSN (online)	1742-5662
ISSN	1742-5689
DOI	10.1098/rsif.2020.0251
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Article ; Online: An investigation of design principles underlying repulsive and attractive gradient sensing and their switching.

Krishnan, J / Alam-Nazki, Aiman

Journal of theoretical biology

2011 Volume 273, Issue 1, Page(s) 80–99

Abstract: ... In this paper we consider cells which exhibit both repulsive and attractive gradient sensing responses and aim ...

Abstract	Many important cellular processes rely on cellular responses to spatially graded signals. This response may be either attractive, indicating a positive bias, or repulsive indicating a negative bias. In this paper we consider cells which exhibit both repulsive and attractive gradient sensing responses and aim to uncover the underlying design principles and features of how the networks are wired which could allow a cell to exhibit both responses. We use a modular approach to examine different configurations which will allow for a cell to exhibit both responses and analyse how this depends on the basic characteristics of gradient sensing and downstream signal propagation. Overall our analysis provides insights into how gradient responses can be switched and the key factors which affect this switching.
MeSH term(s)	Animals ; Models, Biological ; Signal Transduction
Language	English
Publishing date	2011-03-21
Publishing country	England
Document type	Journal Article
ZDB-ID	2972-5
ISSN	1095-8541 ; 0022-5193
ISSN (online)	1095-8541
ISSN	0022-5193
DOI	10.1016/j.jtbi.2010.11.046
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Article ; Online: A mathematical modelling framework for understanding chemorepulsive signal transduction in Dictyostelium.

Alam-Nazki, Aiman / Krishnan, J

Journal of theoretical biology

2010 Volume 266, Issue 1, Page(s) 140–153

Abstract: Chemorepulsion is the process by which an organism or a cell moves in the direction of decreasing chemical concentration. While a few experimental studies have been performed, no mathematical models exist for this process. In this paper we have modelled ... ...

Abstract	Chemorepulsion is the process by which an organism or a cell moves in the direction of decreasing chemical concentration. While a few experimental studies have been performed, no mathematical models exist for this process. In this paper we have modelled gradient sensing, the first subprocess of chemorepulsion, in Dictyostelium discoideum-a well characterized model eukaryotic system. We take the first steps towards achieving a comprehensive mechanistic understanding of chemorepulsion in this system. We have used, as a basis, the biochemical network of the Keizer-Gunnink et al. (2007) to develop the mathematical modelling framework. This network describes the underlying pathways of chemorepellent gradient sensing in D. discoideum. Working within this modelling framework we address whether the postulated interactions of the pathways and species in this network can lead to a chemorepulsive response. We also analyse the possible role of additional regulatory effects (such as additional receptor regulation of enzymes in this network) and if this is necessary to achieve this behaviour. Thus we have investigated the receptor regulation of important enzymes and feedback effects in the network. This modelling framework generates important insights into and testable predictions regarding the role of key components and feedback loops in regulating chemorepulsive gradient sensing, and what factors might be important for generating a chemorepulsive response; it serves as a first step towards a comprehensive mechanistic understanding of this process.
MeSH term(s)	Actin Cytoskeleton/metabolism ; Algorithms ; Chemotaxis/physiology ; Computer Simulation ; Cyclic AMP/analogs & derivatives ; Cyclic AMP/metabolism ; Dictyostelium/physiology ; Diglycerides/metabolism ; Feedback, Physiological/physiology ; GTP-Binding Protein alpha Subunits/metabolism ; Models, Biological ; PTEN Phosphohydrolase/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphatidylinositol 4,5-Diphosphate/metabolism ; Phosphatidylinositol Phosphates/metabolism ; Pseudopodia/metabolism ; Receptors, Cyclic AMP/metabolism ; Signal Transduction/physiology ; Thionucleotides/metabolism ; Type C Phospholipases/metabolism
Chemical Substances	Diglycerides ; GTP-Binding Protein alpha Subunits ; Phosphatidylinositol 4,5-Diphosphate ; Phosphatidylinositol Phosphates ; Receptors, Cyclic AMP ; Thionucleotides ; cyclic AMP receptor cAR1 ; phosphatidylinositol 3,4,5-triphosphate ; 8-((4-chlorophenyl)thio)cyclic-3',5'-AMP (41941-66-6) ; Cyclic AMP (E0399OZS9N) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; PTEN Phosphohydrolase (EC 3.1.3.67) ; Type C Phospholipases (EC 3.1.4.-)
Language	English
Publishing date	2010-09-07
Publishing country	England
Document type	Journal Article
ZDB-ID	2972-5
ISSN	1095-8541 ; 0022-5193
ISSN (online)	1095-8541
ISSN	0022-5193
DOI	10.1016/j.jtbi.2010.05.017
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Article ; Online: An investigation of spatial signal transduction in cellular networks

Alam-Nazki Aiman / Krishnan J

BMC Systems Biology, Vol 6, Iss 1, p

2012 Volume 83

Abstract: Abstract Background Spatial signal transduction plays a vital role in many intracellular processes such as eukaryotic chemotaxis, polarity generation and cell division. Furthermore it is being increasingly realized that the spatial dimension to ... ...

Abstract	Abstract Background Spatial signal transduction plays a vital role in many intracellular processes such as eukaryotic chemotaxis, polarity generation and cell division. Furthermore it is being increasingly realized that the spatial dimension to signalling may play an important role in other apparently purely temporal signal transduction processes. It is increasingly being recognized that a conceptual basis for studying spatial signal transduction in signalling networks is necessary. Results In this work we examine spatial signal transduction in a series of standard motifs/networks. These networks include coherent and incoherent feedforward, positive and negative feedback, cyclic motifs, monostable switches, bistable switches and negative feedback oscillators. In all these cases, the driving signal has spatial variation. For each network we consider two cases, one where all elements are essentially non-diffusible, and the other where one of the network elements may be highly diffusible. A careful analysis of steady state signal transduction provides many insights into the behaviour of all these modules. While in the non-diffusible case for the most part, spatial signalling reflects the temporal signalling behaviour, in the diffusible cases, we see significant differences between spatial and temporal signalling characteristics. Our results demonstrate that the presence of diffusible elements in the networks provides important constraints and capabilities for signalling. Conclusions Our results provide a systematic basis for understanding spatial signalling in networks and the role of diffusible elements therein. This provides many insights into the signal transduction capabilities and constraints in such networks and suggests ways in which cellular signalling and information processing is organized to conform to or bypass those constraints. It also provides a framework for starting to understand the organization and regulation of spatial signal transduction in individual processes.
Keywords	Cellular signal processing ; Spatial signalling ; Signalling motifs ; Global regulation ; Diffusion ; Non-linear dynamics ; Networks ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2012-07-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Covalent Modification Cycles through the Spatial Prism

Alam-Nazki, Aiman / Krishnan, J

Biophysical journal. 2013 Oct. 1, v. 105, no. 7

2013

Abstract	Covalent modification cycles are basic units and building blocks of posttranslational modification and cellular signal transduction. We systematically explore different spatial aspects of signal transduction in covalent modification cycles by starting with a basic temporal cycle as a reference and focusing on steady-state signal transduction. We consider, in turn, the effect of diffusion on spatial signal transduction, spatial analogs of ultrasensitive behavior, and the interplay between enzyme localization and substrate diffusion. Our analysis reveals the need to explicitly account for kinetics and diffusional transport (and localization) of enzymes, substrates, and complexes. It demonstrates a complex and subtle interplay between spatial heterogeneity, diffusion, and localization. Overall, examining the spatial dimension of covalent modification reveals that 1), there are important differences between spatial and temporal signal transduction even in this cycle; and 2), spatial aspects may play a substantial role in affecting and distorting information transfer in modules/networks that are usually studied in purely temporal terms. This has important implications for the systematic understanding of signaling in covalent modification cycles, pathways, and networks in multiple cellular contexts.
Keywords	enzymes ; information exchange ; post-translational modification ; signal transduction
Language	English
Dates of publication	2013-1001
Size	p. 1720-1731.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2013.06.050
Database	NAL-Catalogue (AGRICOLA)

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Article: An investigation of design principles underlying repulsive and attractive gradient sensing and their switching

Krishnan, J / Alam-Nazki, Aiman

Journal of theoretical biology. 2011 Mar. 21, v. 273, no. 1

2011

Abstract: ... In this paper we consider cells which exhibit both repulsive and attractive gradient sensing responses and aim ...

Abstract	Many important cellular processes rely on cellular responses to spatially graded signals. This response may be either attractive, indicating a positive bias, or repulsive indicating a negative bias. In this paper we consider cells which exhibit both repulsive and attractive gradient sensing responses and aim to uncover the underlying design principles and features of how the networks are wired which could allow a cell to exhibit both responses. We use a modular approach to examine different configurations which will allow for a cell to exhibit both responses and analyse how this depends on the basic characteristics of gradient sensing and downstream signal propagation. Overall our analysis provides insights into how gradient responses can be switched and the key factors which affect this switching.
Keywords	cells ; physiological response ; signal transduction
Language	English
Dates of publication	2011-0321
Size	p. 80-99.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	2972-5
ISSN	1095-8541 ; 0022-5193
ISSN (online)	1095-8541
ISSN	0022-5193
DOI	10.1016/j.jtbi.2010.11.046
Database	NAL-Catalogue (AGRICOLA)

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Article: investigation of design principles underlying repulsive and attractive gradient sensing and their switching

Krishnan, J. / Alam-Nazki, Aiman

Journal of theoretical biology

Volume v. 273,, Issue no. 1

Abstract: ... In this paper we consider cells which exhibit both repulsive and attractive gradient sensing responses and aim ...

Abstract	Many important cellular processes rely on cellular responses to spatially graded signals. This response may be either attractive, indicating a positive bias, or repulsive indicating a negative bias. In this paper we consider cells which exhibit both repulsive and attractive gradient sensing responses and aim to uncover the underlying design principles and features of how the networks are wired which could allow a cell to exhibit both responses. We use a modular approach to examine different configurations which will allow for a cell to exhibit both responses and analyse how this depends on the basic characteristics of gradient sensing and downstream signal propagation. Overall our analysis provides insights into how gradient responses can be switched and the key factors which affect this switching.
Keywords	cells ; signal transduction ; physiological response
Language	English
Document type	Article
ISSN	0022-5193
Database	AGRIS - International Information System for the Agricultural Sciences and Technology

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