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Folma Buss

Myosin motor proteins in health and disease

Intracellular transport is driven by motor proteins that use energy derived from ATP hydrolysis to organize cellular compartments and control intracellular transport along cytoskeletal tracks; defects in these fundamental transport processes are linked to a wide range of disorders including deafness, cardiomyopathy, neurodegeneration and cancer. Research in our lab is focused on the cellular function of myosin motors that generate force and move cargo along actin tracks. We are using a variety of cellular, molecular and biochemical approaches to determine how a motor recognizes and selects its cargo and how motor activity and cargo attachment are coordinated. Much of our research has focused on myosins of class I and also class VI (MYO6), a unique highly specialized class of myosin motors that move in reverse direction along actin filaments. Using in situ proximity labelling and functional proteomics we have mapped the interactome of myosins of class I and VI and identified MYO6-associated complexes that highlight the role of this myosin in regulating actin cytoskeleton dynamics. Indeed MYO6 initiates the assembly of F-actin cages around damaged mitochondria, which serves as a quality control mechanism to isolate dysfunctional organelles from the healthy network. Our overall aim is to determine the role(s) of these myosins and their cargo adaptors in cell signalling, cargo transport and cellular homeostasis and why dysfunction is linked to neurodegenerative disorders such as Alzheimer’s, Parkinson’s and motor neuron disease.

 

Buss graphic 2018

Figure 1: The MYO6 interactome was identified using proximity labelling‐based proteomics, highlighting the role of MYO6 in coordinating endosome dynamics and cytoskeletal architecture.


 Kruppa image 2018

 

Figure 2: Mitochondrial homeostasis is maintained by removing dysfunctional, ubiquitinated mitochondria from the network via mitophagy. On the mitochondrial surface, myosin VI (cyan) initiates the assembly of F-actin cages (yellow), which serve as a quality control mechanism to isolate dysfunctional mitochondria (magenta) and thereby prevent their refusion with neighbouring populations.

 

 

Buss lab

Key papers:

O’Loughlin, T, Masters, TA and Buss, F. The MYO6 interactome reveals adaptor complexes coordinating early endosome and cytoskeletal dynamics. EMBO Rep. 19(4) doi: 10.15252/embr.201744884 (2018).

Kruppa AJ, Kishi-Itakura C, Masters TA, Rorbach JE, Grice GL, Kendrick-Jones J, Nathan JA, Minczuk M and Buss F. Myosin VI-dependent actin cages encapsulate Parkin-positive damaged mitochondria. Dev. Cell 44:489-499 (2018).

Masters TA, Tumbarello DA, Chibalina MV, Buss F. MYO6 Regulates Spatial Organization of Signaling Endosomes Driving AKT Activation and Actin Dynamics. Cell Rep. 19, 2088-2101 (2017).

Brooks AB, Humphreys D, Singh V, Davidson AC, Arden SD, Buss F, Koronakis V. MYO6 is targeted by Salmonella virulence effectors to trigger PI3-kinase signaling and pathogen invasion into host cells. Proc. Natl Acad. Sci. USA 114, 3915-3920 (2017).

Masters TA, Buss F. Filopodia formation and endosome clustering induced by mutant plus-end-directed myosin VI. Proc. Natl Acad. Sci. USA 114, 1595-1600 (2017).

Waxse BJ, Sengupta P, Hesketh GG, Lippincott-Schwartz J, Buss F. Myosin VI facilitates connexin 43 gap junction accretion. J. Cell Sci. 130, 827-840 (2017).

Arden SD, Tumbarello DA, Butt T, Kendrick-Jones J, Buss F. Loss of cargo binding in the human myosin VI deafness mutant (R1166X) leads to increased actin filament binding. Biochem J. 473, 3307-3319 (2016).

Tumbarello DA, Manna P, Allen M, Bycroft M, Arden SD, Kendrick-Jones J & Buss F. The autophagy receptor TAX1BP1 and the molecular motor myosin VI are required for clearance of Salmonella typhimurium by autophagy. PLoS Pathogens 11, e1005174. doi: 10.1371/journal.ppat.1005174 (2015).

Brandstaetter, H, Kishi-Itakura, C, Manstein D, Tumbarello D. and Buss F. Loss of functional myosin 1c, a motor protein involved in lipid raft trafficking, disrupts autophagosome-lysosome fusion. Autophagy 10, 2310-23 (2014).

Tumbarello, D. A., Waxse, B. J., Arden, S. D., Bright, N. A., Kendrick-Jones, J. and Buss, F. Autophagy-receptors link myosin VI to autophagosomes to mediate Tom1-dependent autophagosome maturation and fusion with the lysosome.  Nature Cell Biol. 10, 1024–1035 (2012).

Folma Buss

Professor Folma Buss

Department: Clinical Biochemistry

contact:fb207@cam.ac.uk

01223 763348

Plain English

Research in our lab is focused on motor proteins, which are molecular machines that drive cargo along tracks to specific sites in the cell, rather like a train running along a railway network to specific destinations. The cargo is hooked up to the motor with the help of specific adaptor proteins that we have identified in our research. We currently focus on myosins of class I and VI, which have distinct functions in cell transport. It is important to understand the regulation and on/off switches of these molecular machines, as defects in myosin VI for example can cause deafness and also potentially Parkinson’s disease and prostate cancer. Our aim is to identify the precise role of these myosin motors and their adaptor proteins in neurodegenerative disease, with the hope of devising possible diagnostic and therapeutic strategies.

 

Group members

Sue Arden · Janeska de Jonge · Antonina Kruppa · Przemysław Zakrzewski

 

Funding

British Heart Foundation

Medical Research Council

Biotechnology and Biological Sciences Research Council